3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh

ABSTRACT

The invention is directed to a formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2a , R 2b  and R 3 -R 7  are herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.

FIELD OF THE INVENTION

The present invention is directed to novel3-pyrimidinyl-4-yl-oxazolidin-2-one compounds, compositions containingthese compounds, the use of such compounds in the inhibition of mutantIDH proteins having a neomorphic activity and in the treatment ofdiseases or disorders associated with such mutant IDH proteinsincluding, but not limited to, cell-proliferation disorders, such ascancer.

BACKGROUND OF THE INVENTION

Isocitrate dehydrogenase (IDH) is a key family of enzymes found incellular metabolism. They are NADP⁺/NAD⁺ and metal dependentoxidoreductases of the enzyme class EC 1.1.1.42. The wild type proteinscatalyze the oxidative decarboxylation of isocitrate toalpha-ketoglutarate generating carbon dioxide and NADPH/NADH in theprocess. They are also known to convert oxalosuccinate intoalpha-ketoglutarate. Mutations in IDH1 (cytosolic) and IDH2(mitochondrial) have been identified in multiple cancer types including,but not limited to, glioma, glioblastoma multiforme, paraganglioma,supratentorial primordial neuroectodermal tumors, acute myeloid leukemia(AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma,cholangiocarcinoma, peripheral T-cell lymphoma, and melanoma. (See L.Dang et al., Trends Mol. Med., 2010, 16, 387; T. Shibata et al., Am. J.Pathol., 2011, 178(3), 1395; Gaal et al., J. Clin. Endocrinol. Metab.2010; Hayden et al., Cell Cycle, 2009; Balss et al., Acta Neuropathol.,2008). The mutations have been found at or near key residues in theactive site: G97D, R100, R132, H133Q, and A134D for IDH1, and R140 andR172 for IDH2. (See L. Dang et al., Nature, 2009, 462, 739; L. Sellneret al., Eur. J. Haematol., 2011, 85, 457).

These mutant forms of IDH are shown to have a neomorphic activity (alsoknown as a gain of function activity), reducing alpha-ketoglutarate to2-hydroxyglutarate (2-HG). (See P. S. Ward et al., Cancer Cell, 2010,17, 225) In general, production of 2-HG is enantiospecific, resulting ingeneration of the D-enantiomer (also known as R enantiomer or R-2-HG).Normal cells have low native levels of 2-HG, whereas cells harboringthese mutations in IDH1 or IDH2 show significantly elevated levels of2-HG. High levels of 2-HG have been detected in tumors harboring themutations. For example, high levels of 2-HG have been detected in theplasma of patients with mutant IDH containing AML. (See S. Gross et al.,J. Exp. Med., 2010, 207(2), 339). High levels of 2-HG are highlyassociated with tumorigenesis.

Mutant IDH2 is also associated with the rare neurometabolic disorderD-2-hydroxyglutaric aciduria type II (D-2-HGA type II). Germlinemutations were found at R140 in IDH2 in 15 pateints having D-2-HGA typeII. Patients having this disorder also have consistently increasedlevels of D-2-HG in their urine, plasma and cerebrospinal fluid. (SeeKranendijk, M. et al., Science, 2010, 330, 336). Finally, patients withOllier Disease and Mafucci Syndrome (two rare disorders that predisposeto cartilaginous tumors) have been shown to be somatically mosaic forIDH1 and 2 mutations and exhibit high levels of D-2-HG. (See Amary etal., Nature Genetics, 2011 and Pansuriya et al., Nature Genetics, 2011).

Thus, there is a need for small molecule inhibitors of mutant IDHproteins having a neomorphic activity for the treatment of diseases anddisorders associated with these proteins.

SUMMARY OF THE INVENTION

In one aspect, this invention provides for a compound of formula (I)

or a pharmaceutically acceptable salt thereof wherein R¹, R^(2a), R^(2b)and R³-R⁷ are defined below.

In a second aspect, this invention provides for a pharmaceuticalcomposition comprising a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier orexcipient.

In a third aspect, this invention provides for the use of a compound offormula (I), or a pharmaceutically acceptable salt thereof, as aninhibitor of a mutant IDH protein having a neomorphic activity such asreducing alpha-ketoglutarate to 2-hydroxyglutarate (2-HG neomorphicactivity). Suitably, this invention provides for the use of a compoundof formula (I), or a pharmaceutically acceptable salt thereof, as aninhibitor of mutant IDH1 having a neomorphic activity, such as 2-HGneomorphic activity, and/or mutant IDH2 having a neomorphic activity,such as 2-HG neomorphic activity. This invention further provides forthe use of a compound of formula (I), or a pharmaceutically acceptablesalt thereof, as an inhibitor of IDH1 having a mutation at residue 97,100 or 132, for example G97D, R100Q, R132H, R132C, R132S, R132G, R132L,and R132V; and/or an inhibitor of IDH2 having a mutation at residue 140or 172, for example R172K, R172M, R172S, R172G, and R172W.

In a fourth aspect, this invention provides for a method of treating adisease or disorder associated with a mutant IDH protein having aneomorphic activity comprising administration of an effective amount ofa compound according to formula (I), or a pharmaceutically acceptablesalt thereof, to a subject in need thereof. In one embodiment, thedisease or disorder is a cell proliferation disorder, such as cancer. Inanother embodiment, the cancer is brain cancer, such as glioma,glioblastoma multiforme, paraganglioma, and supratentorial primordialneuroectodermal tumors (pNET); leukemia, such as acute myeloid leukemia(AML), myelodysplastic syndrome, and chronic myelogenous leukemia (CML);skin cancer, including melanoma; prostate cancer; thyroid cancer; coloncancer; lung cancer; sarcoma, including central chondrosarcoma, centraland periosteal chondroma; and fibrosarcoma. In another embodiment thedisease or disorder is D-2-hydroxyglutaric aciduria.

In a fifth aspect the invention provides for a compound of formula (I),or a pharmaceutically acceptable salt thereof, in combination withanother therapeutic agent.

These and other aspects of the present invention are described furtherin the following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a compound of formula (I)

wherein:R¹ is hydrogen, methyl or ethyl;R^(2a) is hydrogen, methyl or C₁₋₃ haloalkyl;R^(2b) is OH, halo, C₁₋₆ alkoxy, C₁₋₃ haloalkyl, NH₂, NH(CH₃) orN(CH₃)₂;R³ and R⁴ are each independently hydrogen, methyl or ethyl or R³ and R⁴are joined together forming cyclopropyl, cyclobutyl or oxetanyl;R⁵ and R⁶ are each independently hydrogen, deuterium, halo, —C(O)OCH₃,C₁₋₃ alkyl or C₁₋₃ haloalkyl;

R⁷ is

wherein:

-   -   ring A is a 6 membered heteroaryl ring having one to three        nitrogen atoms;    -   ring B is a 5 membered heteroaryl ring having one to four        heteroatoms each independently selected from the group        consisting of N, O and S;    -   X is N or CH;

each R⁸ is independently hydrogen, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl,C₁₋₃ alkoxy or C₁₋₃ haloalkoxy;

-   -   n is 1 or 2;    -   R⁹ is hydrogen, halo, C₁₋₃ haloalkyl, optionally substituted        C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl, optionally        substituted aryl, optionally substituted 5 or 6 membered        heterocyclic, optionally substituted heteroaryl, —OR^(9a),        —SO₂R^(9a), —C(O)NHR^(9a), CH₂R^(9b) or CHCH₃R^(9b), provided        that when X is N, R⁹ is hydrogen, C₁₋₃ haloalkyl, optionally        substituted C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl,        optionally substituted aryl, optionally substituted heteroaryl,        —SO₂R^(9a) or —C(O)NHR^(9a), wherein:        -   said C₁₋₆ alkyl is optionally substituted with one to three            substituents each independently selected from the group            consisting of: OH, phenyl and phenoxy, and        -   said C₃₋₆ cycloalkyl, 5 or 6 membered heterocyclic, aryl and            heteroaryl are each optionally substituted with one to three            substituents each independently selected from the group            consisting of: halo, hydroxyl, cyano, —NRR, C₁₋₆ alkyl, C₁₋₆            haloalkyl, C₁₋₃ alkoxy, and C₁₋₃ haloalkoxy;    -   R^(9a) is optionally substituted C₁₋₆ alkyl, C₁₋₆ haloalkyl,        optionally substituted C₃₋₆ cycloalkyl, optionally substituted        phenyl, or optionally substituted heterocyclic, wherein:        -   said C₁₋₆ alkyl is optionally substituted with one C₃₋₆            cycloalkyl,        -   said C₃₋₆ cycloalkyl and heterocyclic are each optionally            substituted with one to three substituents each            independently selected from the group consisting of:            hydroxyl, CH₂OH, —NRR, cyano, C₁₋₃ alkyl, C₁₋₃ haloalkyl,            and C₁₋₃ alkoxy, and        -   said phenyl is optionally substituted with one to three            substituents each independently selected from the group            consisting of: halo, hydroxyl, cyano, —NRR, C₁₋₆ alkyl, C₁₋₆            haloalkyl, C₁₋₃ alkoxy, and C₁₋₃ haloalkoxy;    -   R^(9b) is optionally substituted C₃₋₆ cycloalkyl, optionally        substituted phenyl or optionally substituted heterocyclic,        -   said C₃₋₆ cycloalkyl and heterocyclic are each optionally            substituted with one to four substituents each independently            selected from the group consisting of: hydroxyl, CH₂OH,            —NRR, —NRC(O)CH₃, 4 to 6 membered heterocyclic, cyano, halo,            C₁₋₃ alkyl, C₁₋₃ haloalkyl, and C₁₋₃ alkoxy, and        -   said phenyl is optionally substituted with one to three            substituents each independently selected from the group            consisting of: halo, hydroxyl, cyano, C₁₋₆ alkyl, C₁₋₆            haloalkyl, C₁₋₃ alkoxy, and C₁₋₃ haloalkoxy; and

each R is independently selected from the group consisting of H, C₁₋₃alkyl and C₃₋₆ cycloalkyl.

“Alkyl” refers to a monovalent saturated hydrocarbon chain having thespecified number of carbon atoms. For example, C₁₋₆ alkyl refers to analkyl group having from 1 to 6 carbon atoms. Alkyl groups may beoptionally substituted with one or more substituents as defined informula (I). Alkyl groups may be straight or branched. Representativebranched alkyl groups have one, two, or three branches. Examples ofalkyl groups include, but are not limited to, methyl, ethyl, propyl(n-propyl and isopropyl), butyl (n-butyl, isobutyl, sec-butyl, andt-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.

“Alkoxy” refers to any alkyl moiety attached through an oxygen bridge(i.e. a —O—C₁₋₃ alkyl group wherein C₁₋₃ alkyl is as defined herein).Examples of such groups include, but are not limited to, methoxy,ethoxy, and propoxy.

“Aryl” refers to a hydrocarbon ring system having an aromatic ring. Arylgroups are monocyclic ring systems or bicyclic ring systems. Monocyclicaryl ring refers to phenyl. Bicyclic aryl rings refer to naphthyl and torings wherein phenyl is fused to a C₅₋₇ cycloalkyl or C₅₋₇ cycloalkenylring as defined herein. Aryl groups may be optionally substituted withone or more substituents as defined in formula (I).

“Cycloalkyl” refers to a saturated hydrocarbon ring system having thespecified number of carbon atoms. Cycloalkyl groups are monocyclic orbicyclic ring systems. For example, C₃₋₆ cycloalkyl refers to acycloalkyl group having from 3 to 6 carbon atoms. Cycloalkyl groups maybe optionally substituted with one or more substituents as defined informula (I). Examples of cycloalkyl groups include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

“Cycloalkenyl” refers to an unsaturated hydrocarbon ring system havingthe specified number of carbon atoms and having a carbon-carbon doublebond within the ring. For example, C₅₋₇ cycloalkenyl refers to acycloalkenyl group having from 5 to 7 carbon atoms. In certainembodiments, cycloalkenyl groups have one carbon-carbon double bondwithin the ring. In other embodiments, cycloalkenyl groups have morethan one carbon-carbon double bond within the ring. Cycloalkenyl ringsare not aromatic. Cycloalkenyl groups may be optionally substituted withone or more substituents as defined in formula (I).

“Halo” refers to the halogen radicals fluoro, chloro, bromo, and iodo.

“Haloalkyl” refers to an alkyl group wherein at least one hydrogen atomattached to a carbon atom within the alkyl group is replaced with halo.The number of halo substituents includes, but is not limited to, 1, 2,3, 4, 5, or 6 substituents. Haloalkyl includes, but is not limited to,monofluoromethyl, difluoroethyl, and trifluoromethyl.

“Haloalkoxy” refers to a haloalkyl moiety attached through an oxygenbridge (i.e. a —O—C₁₋₃ haloalkyl group wherein C₁₋₃ haloalkyl is asdefined herein). An example of a haloalkoxy group is trifluoromethoxy.

“Heteroaryl” refers to an aromatic ring system containing from 1 to 5heteroatoms. Heteroaryl groups containing more than one heteroatom maycontain different heteroatoms. Heteroaryl groups may be optionallysubstituted with one or more substituents as defined in formula (I).Heteroaryl groups are monocyclic ring systems or are fused bicyclic ringsystems. Monocyclic heteroaryl rings have from 5 to 6 ring atoms.Bicyclic heteroaryl rings have from 8 to 10 member atoms. Bicyclicheteroaryl rings include those ring systems wherein a heteroaryl ring isfused to a phenyl ring. Heteroaryl includes, but is not limited to,pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl(including 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl), thiazolyl,isothiazolyl, thiadiazolyl, furanyl, furazanyl, thienyl, triazolyl,pyridinyl (including 2-, 3-, and 4-pyridinyl), pyrimidinyl, pyridazinyl,pyrazinyl, trazinyl, tetrazinyl, tetrazolyl, indonyl, isoindolyl,indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl,quinoxalinyl, quinazolinyl, benzimidazolyl, benzopyranyl, benzopyranyl,benzoxazolyl, benzoisoxazolyl, benzofuranyl, benzothiazolyl,benzothienyl, naphthyridinyl, 1H-pyrrolo[2,3-b]pyridinyl,tetrazolo[1,5-a]pyridinyl, imidazo[2,1-b][1,3,4]thiadiazolyl and thelike.

“Heteroatom” refers to a nitrogen, oxygen, or sulfur atom.

“Heterocyclic” refers to a 3 to 11 membered saturated or unsaturatedmonocyclic or bicyclic ring containing from 1 to 4 heteroatoms.Heterocyclic ring systems are not aromatic. Heterocyclic groupscontaining more than one heteroatom may contain different heteroatoms.Heterocyclic includes ring systems wherein a sulfur atom is oxidized toform SO or SO₂. Heterocyclic groups may be optionally substituted withone or more substituents as defined in formula (I). Heterocyclic groupsare monocyclic, spiro, or fused or bridged bicyclic ring systems.Monocyclic heterocyclic rings have 3 to 7 ring atoms. Examples ofmonocyclic heterocyclic groups include oxetanyl, tetrahydrofuranyl,dihydrofuranyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl,piperidinyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl,pyrrolidinyl, tetrahydropyranyl, dihydropyranyl, oxathiolanyl,dithiolanyl, 1,3-dioxanyl, 1,3-dithianyl, oxathianyl, thiomorpholinyl,tetrahydro-thiopyran 1,1-dioxide, 1,4-diazepanyl, and the like. Fusedheterocyclic ring systems have from 8 to 11 ring atoms and includegroups wherein a heterocyclic ring is fused to a phenyl ring, aheteroaryl ring or another heterocyclic ring. Examples of fusedheterocyclic rings include 2,3-dihydrobenzo[b][1,4]dioxinyl,benzo[1,3]dioxyl, octahydro-pyrrolo[1,2-a]pyrazinyl,octahydro-pyrido[1,2-a]pyrazinyl, octahydro-pyrrolo[3,4-c]pyrrolyl,5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazinyl and the like. Examples ofbridged heterocyclic groups include 3,8-diaza-bicyclo[3.2.1]octanyl,3,8-diaza-bicyclo[4.2.0]octanyl and the like. Examples of spiroheterocyclic groups include 4,7-diaza-spiro[2.5]octanyl and the like.

“5-6 membered heterocylic” refers to a heterocyclic group as definedabove, having 5 or 6 ring atoms and containing from 1 to 4 heteroatoms.

“Optionally substituted” indicates that a group, such as an alkyl,cycloalkyl, heteroaryl, heterocyclic, phenyl, and benzyl may beunsubstituted or the group may be substituted with one or moresubstituents as defined in formula (I).

“Pharmaceutically acceptable” means a compound which is suitable forpharmaceutical use. Salts and solvates (e.g. hydrates and hydrates ofsalts) of compounds of the invention which are suitable for use inmedicine are those where in the counterion or associated solvent ispharmaceutically acceptable. However, salts and solvates havingnon-pharmaceutically acceptable counterions or associated solvents arewithin the scope of the present invention, for example, for use asintermediates in the preparation of other compounds of the invention andtheir pharmaceutically acceptable salts and solvates.

“Substituted” in reference to a group such as alkyl, phenyl, benzyl,heteroaryl, and heterocyclic, indicates that one or more hydrogen atomsattached to an atom within the group is replaced with a substituentselected from the group of defined substituents. It should be understoodthat the term “substituted” includes the implicit provision that suchsubstitution be in accordance with permitted valence of the substitutedatom and the substituent, and that the substitution results in a stablecompound (i.e. one that does not spontaneously undergo transformation,for example, by hydrolysis, rearrangement, cyclization, or eliminationand that is sufficiently robust to survive isolation from a reactionmixture). When it is stated that a group may contain one or moresubstituents, one or more (as appropriate) atoms within the group may besubstituted. In addition, a single atom within the group may besubstituted with more than one substituent as long as such substitutionis accordance with the permitted valence of the atom. Suitablesubstituents are defined for each substituted or optionally substitutedgroup.

The skilled artisan will appreciate that salts, includingpharmaceutically acceptable salts, of the compounds according to formula(I) may be prepared. These salts may be prepared in situ during thefinal isolation and purification of the compound, or by separatelyreacting the purified compound in its free acid or free base form with asuitable base or acid, respectively.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable. Lists of additional suitable salts can be found, e.g., in“Remington's Pharmaceutical Sciences”, 20th ed., Mack PublishingCompany, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Solvates, including pharmaceutically acceptable solvates, of thecompounds of formula (I) may also be prepared. “Solvate” refers to acomplex of variable stoichiometry formed by a solute and solvent. Suchsolvents for the purpose of the invention may not interfere with thebiological activity of the solute. Examples of suitable solventsinclude, but are not limited to, water, MeOH, EtOH, and AcOH. Solvateswherein water is the solvent molecule are typically referred to ashydrates. Hydrates include compositions containing stoichiometricamounts of water, as well as compositions containing variable amounts ofwater.

The compounds of formula (I), including salts and solvates thereof, mayexist in crystalline forms, non-crystalline forms, or mixtures thereof.The compound or salt or solvate thereof may also exhibit polymorphism,i.e. the capacity of occurring in different crystalline forms. Thesedifferent crystalline forms are typically known as “polymorphs”.Polymorphs have the same chemical composition but differ in packing,geometrical arrangement, and other descriptive properties of crystallinesolid state. Polymorphs, therefore, may have different physicalproperties such as shape, density, hardness, deformability, stability,and dissolution properties. Polymorphs typically exhibit differentmelting points, IR spectra, and X-ray powder diffraction patterns, allof which may be used for identification. One of ordinary skill in theart will appreciate that different polymorphs may be produced, forexample, by changing or adjusting the conditions used incrystallizing/recrystallizing a compound of formula (I).

The invention also includes various isomers of the compounds of formula(I). “Isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of formula (I) may have one ormore asymmetric carbon atom and may occur as racemates, racemic mixturesand as individual enantiomers or diastereomers. All such isomeric formsare included within the present invention, including mixtures thereof,unless specifically indicated otherwise. If the compound contains adouble bond, the substituent may be in the E or Z configuration. If thecompound contains a disubstituted cycloalkyl, the cycloalkyl substituentmay have a cis- or trans-configuration. All tautomeric forms are alsointended to be included.

Any asymmetric atom (e.g., carbon or the like) of a compound of formula(I) can be present in racemic or enantiomerically enriched, for examplethe (R)-, (S)- or (R,S)-configuration. In certain embodiments, eachasymmetric atom has at least 50% enantiomeric excess, at least 60%enantiomeric excess, at least 70% enantiomeric excess, at least 80%enantiomeric excess, at least 90% enantiomeric excess, at least 95%enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or(S)-configuration. Substituents at atoms with unsaturated double bondsmay, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of formula (I) can be in the formof one of the possible isomers, rotamers, atropisomers, tautomers ormixtures thereof, for example, as substantially pure geometric (cis ortrans) isomers, diastereomers, optical isomers, racemates or mixturesthereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical isomers by known methods, e.g., by separationof the diastereomeric salts thereof, obtained with an optically activeacid or base, and liberating the optically active acidic or basiccompound. In particular, a basic moiety may thus be employed to resolvethe compounds of the present invention into their optical isomers, e.g.,by fractional crystallization of a salt formed with an optically activeacid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaricacid, di-O,O′-p-toluoyl tartaric acid, mandelic acid, malic acid orcamphor-10-sulfonic acid. Racemic products can also be resolved bychiral chromatography, e.g., high pressure liquid chromatography (HPLC)using a chiral adsorbent.

The invention includes unlabeled forms as well as isotopically labeledforms of compounds of formula (I). Isotopically labeled compounds havestructures depicted by the formulas given herein except that one or moreatoms are replaced by an atom having a selected atomic mass or massnumber. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵I respectively. The invention includesvarious isotopically labeled compounds as defined herein, for examplethose into which radioactive isotopes, such as ³H and ¹⁴C, or those intowhich non-radioactive isotopes, such as ²H and ¹³C are present. Suchisotopically labelled compounds are useful in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F or labeled compound may be particularlydesirable for PET or SPECT studies. Isotopically-labeled compounds offormula (I) can generally be prepared by conventional techniques knownto those skilled in the art or by processes analogous to those describedin the accompanying Examples and Preparations using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

Furthermore, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Representative Embodiments

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide for further embodiments.

In one embodiment of the present invention R¹ is hydrogen.

In another embodiment of the present invention R^(2a) is hydrogen ormethyl. Suitably R^(2a) is methyl.

In another embodiment of the present invention R^(2b) is OH, fluoro,methoxy, t-butoxy, CHF₂, CF₃, NH₂ or NH(CH₃). Suitably R^(2b) is OH,fluoro or NH₂.

In another embodiment of the present invention R³ and R⁴ are eachhydrogen.

In another embodiment of the present invention R⁵ is hydrogen or halo.Suitably R⁵ is hydrogen, fluoro or chloro. More suitably R⁵ is hydrogenor fluoro.

In another embodiment of the present invention R⁶ is hydrogen, halo,methyl, CH₂F, CHF₂, or CF₃. Suitably R⁶ is hydrogen, fluoro, chloro,methyl, CH₂F, CHF₂, or CF₃. More suitably R⁶ is hydrogen or methyl.

In another embodiment of the present invention R⁵ is hydrogen and R⁶ ishydrogen, halo, methyl, CH₂F, CHF₂, or CF₃. Suitably R⁵ is hydrogen andR⁶ is hydrogen, fluoro, chloro, methyl, CH₂F, CHF₂, or CF₃. Moresuitably R⁵ is hydrogen and R⁶ is hydrogen or methyl.

In another embodiment of the present invention R⁶ is hydrogen and R⁵ ishydrogen or halo. Suitably R⁶ is hydrogen and R⁵ is hydrogen, fluoro orchloro. More suitably R⁶ is hydrogen and R⁵ is hydrogen or fluoro.

In another embodiment R⁵ and R⁶ are both hydrogen.

In another embodiment R⁷ is

In another embodiment R⁷ is

In another embodiment R⁸ is hydrogen, fluoro, chloro or methyl and nis 1. In another embodiment each R⁸ is independently fluoro or chloroand n is 2.

In another embodiment R⁹ is hydrogen, halo, C₁₋₃ haloalkyl, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl. SuitablyR⁹ is hydrogen, halo, CF₂H, CF₃, CF₂CH₃, C(CH₃)₂F, C₁₋₆ alkyl optionallysubstituted with one substituent selected from the group consisting of:OH, phenyl and phenoxy, or C₃₋₆ cycloalkyl optionally substituted withone substituent selected from the group consisting of: cyano, C₁₋₃alkyl, and C₁₋₃ alkoxy. Suitably R⁹ is hydrogen, halo, CF₂H, CF₃,CF₂CH₃, C(CH₃)₂F, C₁₋₃ alkyl optionally substituted with one substituentselected from the group consisting of: OH, phenyl and phenoxy group, orcyclopropyl optionally substituted with one substituent selected fromthe group consisting of: cyano, C₁₋₃ alkyl, and C₁₋₃ alkoxy.

In another embodiment R⁹ is phenyl or 2,3-dihydro-1H-indenyl optionallysubstituted with one or two substituents each independently selectedfrom the group consisting of: fluoro, chloro, bromo, cyano, methoxy,CH₂OH, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₃ haloalkoxy.

In another embodiment R⁹ is phenyl optionally substituted with one ortwo substituents each independently selected from the group consistingof: fluoro, chloro, bromo, cyano, methoxy, CH₂OH, C₁₋₄ alkyl, C₁₋₄haloalkyl and C₁₋₃ haloalkoxy. Suitably R⁹ is phenyl optionallysubstituted with one or two substituents each independently selectedfrom the group consisting of: fluoro, chloro, bromo, cyano, methoxy,CH₂OH, C₁₋₄ alkyl, CF₂H, CF₃, C(CH₃)₂CF₃, OCF₃, —OCH₂CF₃, and —OCHF₂.Suitably R⁹ is phenyl substituted in the para position with chloro,fluoro, methyl, cyano, CF₃ or isopropyl. Suitably R⁹ is phenylsubstituted in the para position with chloro, CF₃ or isopropyl.

In another embodiment R⁹ is optionally substituted heteroaryl. SuitablyR⁹ is optionally substituted pyrazolyl, pyridinyl, indolyl orisoquinolinyl. Suitably R⁹ is pyrazolyl or pyridinyl optionallysubstituted with one or two substituents each independently selectedfrom the group consisting of halo, C₁₋₆ alkyl and C₁₋₆ haloalkyl, forexample, fluoro, methyl and CF₃ or C(CH₃)₂CF₃.

In another embodiment R⁹ is —OR^(9a) wherein R^(9a) is optionallysubstituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, optionally substituted phenyl,or optionally substituted 5 or 6 membered heterocyclic. Suitably R^(9a)is tetrahydrofuranyl, CF₃, CHF₂, CHCF₃, C₁₋₆ alkyl optionallysubstituted with one cyclopropyl, or phenyl optionally substituted withone halo.

In another embodiment R⁹ is —SO₂R^(9a) wherein R^(9a) is C₁₋₆ alkyl.

In another embodiment R⁹ is —C(O)NHR^(9a) wherein R^(9a) is optionallysubstituted C₃₋₆ cycloalkyl. Suitably R⁹ is —C(O)NHR^(9a) wherein R^(9a)is cyclopentyl.

In another embodiment R⁹ is CH₂R^(9b) wherein R^(9b) is optionallysubstituted heterocyclic. Suitably R^(9b) is optionally substituted 5 to6 membered heterocyclic. Suitably R^(9b) is piperidinyl, piperazinyl ormorpholinyl each of which is optionally substituted with one to foursubstituents each independently selected from the group consisting of:hydroxyl, halo, CH₂OH, —NRR, cyano, C₁₋₃ alkyl, C₁₋₃ haloalkyl, and C₁₋₃alkoxy. Suitably R^(9b) is piperidinyl, piperazinyl or morpholinyl eachof which is optionally substituted with one to three substituents eachindependently selected from the group consisting of: hydroxyl, CH₂OH,fluoro, NH₂, N(CH₃)₂, NHCH₃, methyl, and CF₃.

In another embodiment of the present invention each R is independentlyselected from the group consisting of: H, C₁₋₃ alkyl.

Another embodiment of the present invention is a compound according toformula (II).

Another embodiment of the present invention is a compound according toformula (III).

wherein R^(2b) is OH, NH₂ or fluoro.

Another embodiment of the present invention is a compound according toformula (IV).

wherein R^(2b) is OH or NH₂. Suitably R^(2b) is OH. Suitably R^(2b) isNH₂.

Another embodiment of the present invention is a compound according toformula (IV), wherein:

R^(2b) is OH;

R⁵ is hydrogen or fluoro;

R⁶ is hydrogen, chloro, methyl or CH₂F;

R⁷ is

R⁸ is hydrogen, methyl or fluoro;n is 1 or 2; and

R⁹ is methylcyclopropyl, isobutoxy, phenyl optionally substituted withone or two substituents each independently selected from the groupconsisting of: fluoro, chloro, bromo, C₁₋₄ alkyl, CF₂H, and CF₃, orpyridinyl optionally substituted with one or two substituents eachindependently selected from the group consisting of: methyl, CF₃ andC(CH₃)₂CF₃; Suitably R⁵ is hydrogen and R⁶ is chloro, methyl or CH₂F orR⁶ is hydrogen and R⁵ is fluoro. Suitably R⁵ is hydrogen and R⁶ are bothhydrogen.

Another embodiment of the present invention is a compound according toformula (V).

Another embodiment of the present invention is a compound according toformula (V) wherein:

R⁵ is hydrogen or fluoro;R⁶ is hydrogen;

R⁷ is

R⁸ is hydrogen or methyl;n is 1; andR⁹ is phenyl optionally substituted with one chloro.

Another embodiment of the present invention is a compound according toformula (VI)

wherein:R^(2b) is fluoro;R⁵ is hydrogen or fluoro;R⁶ is hydrogen;

R⁷ is

R⁸ is hydrogen or methyl;n is 1; andR⁹ is phenyl optionally substituted with one chloro; or apharmaceutically acceptable salt thereof.Preferred compounds of the invention include:

-   (R)-4-((R)-1-hydroxy(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-onethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(6-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-chloro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-chloro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(3-chloro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-{2-[((R)1-(3-(3-fluoro-4-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl]amino}pyrimidin-4-yl}-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;-   (R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-5-fluoro-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;-   (R)-3-(5-fluoro-2-(((S)-1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(4-(4-bromophenyl)thiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (4R)-3-(5-fluoro-2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-(fluoromethyl)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(2-(4-(difluoromethyl)phenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)    oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(6-chloro-2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(2,5-difluoro-4-(2-methylpyridin-4-yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(5-fluoro-2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(6-chloro-2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one;-   (S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)    amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)    thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)    isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)    amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-fluoroethyl)    oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-2-methyl-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)    oxazolidin-2-one;-   (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)    amino)pyrimidin-4-yl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one;-   (S)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one;-   (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (R)-3-(5-fluoro-2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(3-chloro-4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one;    and-   (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one.

Certain compounds of the present invention were found to have improvedpreclinical properties. For example, certain compounds of the presentinvention were found to have maintained potency against mIDH1 (forexample IDH R132H and/or R132C) in biochemical and/or cellular activityassays, while at the same time improving in-vitro absorption,distribution, metabolism and excretion (ADME) properties. For example,certain compounds of the present invention were found to have reducedclearance rates in rat and/or mouse and/or human in vitro livermicrosomal stability assays. Stability in the presence of livermicrosomes is important because it can be predictive of in-vivoclearance, and therefore also be predictive of whether or not a compoundwill have an adequate systemic exposure profile in the human body toeffect the desired pharmacological response. Lower clearance rates, i.e.the more stable the compound is in the presence of liver microsomes invitro, suggests the compound is more likely to have adequate systemicexposure in humans.

General Synthetic Procedures

The compounds of the present invention may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the Schemes given below.

The compounds of formula (I) may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes. In the schemes described below, it is well understood thatprotecting groups for sensitive or reactive groups are employed wherenecessary in accordance with general principles or chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, Third edition, Wiley, New York 1999). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selectionprocesses, as well as the reaction conditions and order of theirexecution, shall be consistent with the preparation of compounds offormula (I).

Those skilled in the art will recognize if a stereocenter exists in thecompounds of formula (I). Accordingly, the present invention includesboth possible stereoisomers and includes not only racemic compounds butthe individual enantiomers and/or diastereomers as well. When a compoundis desired as a single enantiomer or diastereomer, it may be obtained bystereospecific synthesis or by resolution of the final product or anyconvenient intermediate. Resolution of the final product, anintermediate, or a starting material may be effected by any suitablemethod known in the art. See, for example, “Stereochemistry of OrganicCompounds” by E. L. Eliel, S. H. Wilen, and L. N. Mander(Wiley-Interscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

wherein R² is CH₂R^(2a)R^(2b)Non-commercial aminoacids can be prepared following the procedures ofScheme 1. Conversion of ketone 1 to the correspondingimidazolidine-2,4-dione 2 followed by hydrolysis provides aminoacid 3.

When aminoalcohol, precursor of oxazolidinone, is not commerciallyavailable, it can be prepared from aminoacid 3 following the proceduresof Scheme 2. When R³=R⁴, protected aminoester 5 is treated with anappropriate Grignard reagent to give protected aminoalcohol 6 which goesthrough basic or acidic deprotection step. When R³=R⁴, protectedaminoacid 8 is converted into Weinreb amide 9 which is treated withdifferent Grignard reagents sequentially to provide protectedaminoalcohol 10. Either basic or acidic deprotection of 10 gives 11.Insertion of CO unit into 7 or 11 to provide oxazolidinone 12 isaccomplished with several reagents, including (but not limited to)triphosgene, Et₂CO₃ or N—N′-darbonyldiimidazole, as shown in Scheme 2.

Oxazolidinone 12 is coupled with dihalogen-pyrimidine 13 in the presenceof NaH and the resulting 14 is treated with primary amine 15 underseveral different reaction conditions as shown in Scheme 3 to provide16.

Alternately intermediate 14 can be prepared by coupling the aminoalcohol 11 and dihalogen-pyrimidine 13 in the presence of a base such asdiisopropylethyl amine resulting in intermediate 17 which can be treatedwith triphosgene in the presence of a base such as 2,6-lutidineresulting in intermediate 14.

Intermediate 14 can undergo modification of functional groups on R¹, R²,R³ or R⁴ prior to transformation to compound 16 as described in Scheme3.

Methods of Use

The compounds of the present invention are inhibitors of a mutant IDHprotein having a neomorphic activity and are therefore useful in thetreatment of diseases or disorders associated with such proteinsincluding, but not limited to, cell proliferation disorders, such ascancer.

Examples of a mutant IDH protein having a neomorphic activity are mutantIDH1 and mutant IDH2. A neomorphic activity associated with mutant IDH1and mutant IDH2 is the ability to produce 2-hydroxyglutarate (2-HGneomorphic activity), specifically R-2-HG (R-2-HG neomorphic activity).Mutations in IDH1 associated with 2-HG neomorphic activity, specificallyR-2-HG neomorphic activity, include mutations at residues 97, 100, and132, e.g. G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V.Mutations in IDH2 associated with 2-HG neoactivity, specifically R-2-HGneomorphic activity, include mutations at residues 140 and 172, e.g.R140Q, R140G, R172K, R172M, R172S, R172G, and R172W.

Cell-proliferation disorders associated with a mutant IDH protein havinga neomorphic activity include, but are not limited to, cancer. Examplesof such cancers include Acute Lymphoblastic Leukemia, Adult; AcuteLymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult;Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood;AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer;Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; BileDuct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood;Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain StemGlioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma,Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor,Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor,Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; BrainTumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; BrainTumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor,Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; BreastCancer, Childhood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids,Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor,Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell;Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary;Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/MalignantGlioma, Childhood; Cervical Cancer; Childhood Cancers; ChronicLymphocytic Leukemia; Chronic Myelogenous Leukemia; ChronicMyeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths;Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma;Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian;Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family ofTumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ CellTumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma;Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach)Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal CarcinoidTumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor,Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor;Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway andHypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular(Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer,Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma,Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer;Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma;Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; KidneyCancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, AcuteLymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood;Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood;Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia,Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary);Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; LungCancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; LymphoblasticLeukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma,AIDS-Related; Lymphoma, Central Nervous System (Primary); Lymphoma,Cutaneous T-Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's,Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma,Non-Hodgkin's, Adult; Lymphoma, Non-Hodgkin's, Childhood; Lymphoma,Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central NervousSystem; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; MalignantMesothelioma, Adult; Malignant Mesothelioma, Childhood; MalignantThymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular;Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous NeckCancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome,Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides;Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; MyeloidLeukemia, Childhood Acute; Myeloma, Multiple; MyeloproliferativeDisorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer;Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma;Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood;Non-Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer;Oral Cancer, Childhood; Oral Cavity and Lip Cancer; OropharyngealCancer; steosarcoma/Malignant Fibrous Histiocytoma of Bone; OvarianCancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor;Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; PancreaticCancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus andNasal Cavity Cancer; Parathyroid Cancer; Penile Cancer;Pheochromocytoma; Pineal and Supratentorial Primitive NeuroectodermalTumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/MultipleMyeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer;Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma;Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult;Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; RenalCell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis andUreter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma,Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood;Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma(Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma,Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, SoftTissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood;Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell LungCancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft TissueSarcoma, Childhood; Squamous Neck Cancer with Occult Primary,Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer,Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood;T-Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood;Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood;Transitional Cell Cancer of the Renal Pelvis and Ureter; TrophoblasticTumor, Gestational; Unknown Primary Site, Cancer of, Childhood; UnusualCancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer;Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway andHypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macroglobulinemia; and Wilms' Tumor.

In another embodiment the cancer associated with a mutant IDH proteinhaving a neomorphic activity is brain cancer, such as astrocytic tumor(e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma,diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplasticastrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma,secondary glioblastoma, primary adult glioblastoma, and primarypediatric glioblastoma); oligodendroglial tumor (e.g.,oligodendroglioma, and anaplastic oligodendroglioma); oligoastrocytictumor (e.g., oligoastrocytoma, and anaplastic oligoastrocytoma);ependymoma (e.g., myxopapillary ependymoma, and anaplastic ependymoma);medulloblastoma; primitive neuroectodermal tumor, schwannoma,meningioma, meatypical meningioma, anaplastic meningioma; and pituitaryadenoma. In another embodiment, the brain cancer is glioma, glioblastomamultiforme, paraganglioma, or suprantentorial primordial neuroectodermaltumors (sPNET).

In another embodiment the cancer associated with a mutant IDH proteinhaving a neomorphic acitvity is leukemia, such as acute myeloid leukemia(AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia(CML), myeloproliferative neoplasm (MPN), MDS.MPN including chronicmyelomonocytic leukemia, post MDS AML, post MPN AML, post MDS/MPN AML,del(5q)-associated high risk MDS or AML, blast-phase chronic myelogenousleukemia, angioimmunoblastic lymphoma and acute lymphoblastic leukemia.

In another embodiment the cancer associated with a mutant IDH proteinhaving a neomorphic activity is skin cancer, including melanoma.

In another embodiment the cancer associated with a mutant IDH proteinhaving a neomorphic activity is prostate cancer, thyroid cancer, coloncancer, or lung cancer.

In another embodiment the cancer associated with a mutant IDH proteinhaving a neomorphic activity is sarcoma, including centralchondrosarcoma, central and periosteal chondroma, and fibrosarcoma.

In another embodiment the cancer associated with a mutant IDH proteinhaving a neomorphic activity is cholangiocarcinoma.

Another disease or disorder associated with a mutant IDH protein havingR-2-HG neomorphic activity is D-2-hydroxyglutaric aciduria.

Another disease or disorder associated with a mutant IDH protein havingR-2-HG neomorphic activity is Oiller disease and Mafucci syndrome.

As used herein the term “neomorphic activity” refers to a gain of novelactivity of a protein that the wild-type protein does not have or doesnot exhibit to a significant degree. For example, a neomorphic activityassociated with a mutant form of IDH1 and IDH2 is the ability to reducealpha-ketoglutarate to 2-hydroxyglutarate (i.e. 2-HG, specificallyR-2-HG). The wild type form of IDH1 and IDH2 does not have the abilityto reduce alpha-ketoglutarate to 2-hydroxyglutarate (i.e. 2-HG,specifically R-2-HG) or if it does have this ability, it does notproduce significant (i.e. harmful or disease causing) amounts of 2-HG.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a primate. In yet other embodiments, the subject is ahuman.

As used herein, the term “therapeutically effective amount” in referenceto a compound of the invention means an amount of the compoundsufficient to treat the subject's disease or condition, but low enoughto avoid serious sides effects (at a reasonable benefit/risk ratio)within the scope of sound medical judgment. A therapeutically effectiveamount of a compound will vary with the particular compound chosen (e.g.consider the potency, efficacy, and half-life of the compound); theroute of administration chosen; the condition being treated; theseverity of the condition being treated; the age, size, weight, andphysical condition of the subject being treated; the medical history ofthe subject being treated; the duration of the treatment; the nature ofthe concurrent therapy; the desired therapeutic effect; and like factorsand can be routinely determined by the skilled artisan.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

The compounds of the present invention may be administered by anysuitable route including oral and parenteral administration. Parenteraladministration is typically by injection or infusion and includesintravenous, intramuscular, and subcutaneous injection or infusion.

The compounds of the invention may be administered once or according toa dosing regimen wherein a number of doses are administered at varyingintervals of time for a given period of time. For example, doses may beadministered one, two, three, or four times per day. Doses may beadministered until the desired therapeutic effect is achieved orindefinitely to maintain the desired therapeutic effect. Suitable dosingregimens for a compound of the invention depend on the pharmacokineticproperties of that compound, such as absorption, distribution and halflife which can be determined by the skilled artisan. In addition,suitable dosing regimens, including the duration such regimens areadministered, for a compound of the invention depend on the disease orcondition being treated, the severity of the disease or condition, theage and physical condition of the subject being treated, the medicalhistory of the subject being treated, the nature of concurrent therapy,the desired therapeutic effect, and like factors within the knowledgeand expertise of the skilled artisan. It will be further understood bysuch skilled artisans that suitable dosing regimens may requireadjustment given an individual subject's response to the dosing regimenor over time as the individual subject needs change. Typical dailydosages may vary depending upon the particular route of administrationchosen. Typical daily dosages for oral administration, to a humanweighing approximately 70 kg would range from about 5 mg to about 500 mgof a compound of formula (I).

One embodiment of the present invention provides for a method oftreating a disease or disorder associated with a mutant form of IDHhaving a neomorphic activity comprising administration of atherapeutically effective amount of a compound of formula (I) to asubject in need of treatment thereof. In one embodiment, the disease ordisorder associated with a mutant form of IDH having a neomorphicactivity is a cell proliferation disorder. In another embodiment, thecell proliferation disorder is cancer. In another embodiment, the canceris a cancer associated with mutant IDH1 having 2-HG neomorphic activityor mutant IDH2 having 2-HG neomorphic activity. In another embodimentthe neomorphic activity is R-2-HG neomorphic activity. In anotherembodiment the cancer is associated with mutant IDH1 having 2-HG orR-2-HG neomorphic activity having a mutation at residues 97, 100, or132, such as G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V.In another embodiment the cancer is associated with mutant IDH2 having2-HG or R-2-HG neomorphic activity having a mutation at residues 140 or172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W. Inanother embodiment the cancer is brain cancer, leukemia, skin cancer,prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma.In another embodiment the cancer is glioma, glioblastoma multiforme,paraganglioma, suprantentorial primordial neuroectodermal tumors, acutemyeloid leukemia, myelodysplastic syndrome, chronic myelogenousleukemia, melanoma, prostate, thyroid, colon, lung, centralchondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma,and cholangiocarcinoma.

Another embodiment of the present invention provides for a method oftreating a disease or disorder associated with a mutant form of IDHhaving R-2-HG neomorphic activity comprising administration of atherapeutically effective amount of a compound according to formula (I)to a subject in need thereof wherein the disease or disorder isD-2-hydroxyglutaric aciduria, Ollier Disease, or Mafucci Syndrome.

Another embodiment of the present invention provides for the use of acompound of formula (I) in therapy. In a further embodiment the therapyis a disease or disorder associated with a mutant form of IDH having aneomorphic activity. In another embodiment the therapy is a cellproliferation disorder associated with a mutant form of IDH having aneomorphic activity. In another embodiment the therapy is cancer. Inanother embodiment the therapy is a cancer associated with a mutant IDHprotein having a neomorphic activity, such as mutant IDH1 having 2-HGneomorphic activity or mutant IDH2 having 2-HG neomorphic activity. Inanother embodiment the neomorphic activity is R-2-HG neomorphicactivity. In another embodiment the cancer is associated with mutantIDH1 having 2-HG or R-2-HG neomorphic activity having a mutation atresidues 97, 100, or 132, such as G97D, R100Q, R132H, R132C, R132S,R132G, R132L, and R132V. In another embodiment the cancer is associatedwith mutant IDH2 having 2-HG or R-2-HG neomorphic activity having amutation at residue at residues R140 or 172, e.g. R140Q, R140G, R172K,R172M, R172S, R172G, and R172W. In another embodiment the cancer isbrain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer,colon cancer, lung cancer or sarcoma. In another embodiment the canceris glioma, glioblastoma multiforme, paraganglioma, suprantentorialprimordial neuroectodermal tumors, acute myeloid leukemia,myelodysplastic syndrome, chronic myelogenous leukemia, melanoma,prostate, thyroid, colon, lung, central chondrosarcoma, central andperiosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.

Another embodiment of the present invention provides for the use of acompound of formula (I) in therapy wherein the therapy isD-2-hydroxyglutaric aciduria, Ollier Disease, or Mafucci Syndrome.

Another embodiment of the present invention provides for the use of acompound according to formula (I) in the manufacture of a medicament forthe treatment of disease or disorder associated with a mutant form ofIDH having a neomorphic activity. In one embodiment the disease ordisorder associated with a mutant form of IDH having a neomorphicactivity is a cell proliferation disorder. In another embodiment, thecell proliferation disorder is cancer. In another embodiment the canceris a cancer associated with a mutant IDH protein having a neomorphicactivity, such as mutant IDH1 having 2-HG neomorphic activity or mutantIDH2 having 2-HG neomorphic activity. In another embodiment theneomorphic activity is R-2-HG neomorphic activity. In another embodimentthe cancer is associated with mutant IDH1 having 2-HG or R-2-HGneomorphic activity having a mutation at residues 97, 100, or 132, suchas G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V. In anotherembodiment the cancer is associated with mutant IDH2 having 2-HG orR-2-HG neomorphic activity having a mutation at residue at residues 140or 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W. Inanother embodiment the cancer is brain cancer, leukemia, skin cancer,prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma.In another embodiment the cancer is glioma, glioblastoma multiforme,paraganglioma, suprantentorial primordial neuroectodermal tumors, acutemyeloid leukemia, myelodysplastic syndrome, chronic myelogenousleukemia, melanoma, prostate, thyroid, colon, lung, centralchondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma,and cholangiocarcinoma.

Another embodiment of the present invention provides for the use of acompound according to formula (I) in the manufacture of a medicament forthe treatment of disease or disorder associated with a mutant form ofIDH having R-2-HG neomorphic activity wherein the disease or disorder isD-2-hydroxyglutaric aciduria, Ollier Disease, or Mafucci Syndrome.

Another embodiment of the present invention provides for a compound offormula (I) for use in therapy. In a further embodiment the therapy is adisease or disorder associated with a mutant form of IDH having aneomorphic activity. In another embodiment the therapy is a cellproliferation disorder associated with a mutant form of IDH having aneomorphic activity. In another embodiment the therapy is cancer. Inanother embodiment the therapy is a cancer associated with a mutant IDHprotein having a neomorphic activity, such as mutant IDH1 having 2-HGneomorphic activity or mutant IDH2 having 2-HG neomorphic activity. Inanother embodiment the neomorphic activity is R-2-HG neomorphicactivity. In another embodiment the cancer is associated with mutantIDH1 having 2-HG or R-2-HG neomorphic activity having a mutation atresidues 97, 100, or 132, such as G97D, R100Q, R132H, R132C, R132S,R132G, R132L, and R132V. In another embodiment the cancer is associatedwith mutant IDH2 having 2-HG or R-2-HG neomorphic activity having amutation at residue at residues R140 or 172, e.g. R140Q, R140G, R172K,R172M, R172S, R172G, and R172W. In another embodiment the cancer isbrain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer,colon cancer, lung cancer or sarcoma. In another embodiment the canceris glioma, glioblastoma multiforme, paraganglioma, suprantentorialprimordial neuroectodermal tumors, acute myeloid leukemia,myelodysplastic syndrome, chronic myelogenous leukemia, melanoma,prostate, thyroid, colon, lung, central chondrosarcoma, central andperiosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.

Another embodiment of the present invention provides for a compound offormula (I) for use in therapy wherein the therapy isD-2-hydroxyglutaric aciduria, Ollier Disease, or Mafucci Syndrome.

Compositions

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I) and a pharmaceuticallyacceptable carrier or excipient.

The pharmaceutical compositions of the invention may be prepared andpackaged in bulk form wherein a therapeutically effective amount of acompound of the invention can be extracted and then given to a subject,such as with powders or syrups. Alternatively, the pharmaceuticalcompositions of the invention may be prepared and packaged in unitdosage form wherein each physically discrete unit contains atherapeutically effective amount of a compound of the invention. Whenprepared in unit dosage form, the pharmaceutical compositions of theinvention typically contain from about 5 mg to 500 mg of a compound offormula (I).

As used herein the term “pharmaceutically acceptable carrier orexcipient” means a pharmaceutically acceptable material, composition orvehicle that, for example, are involved in giving form or consistency tothe pharmaceutical composition. Each excipient must be compatible withthe other ingredients of the pharmaceutical composition when commingledsuch that interactions which would substantially reduce the efficacy ofthe compound of the invention when administered to a subject andinteractions which would result in pharmaceutical compositions that arenot pharmaceutically acceptable are avoided. In addition, each excipientmust, of course, be of sufficiently high purity to render itpharmaceutically acceptable.

The compound of the invention and the pharmaceutically acceptablecarrier or excipient(s) will typically be formulated into a dosage formadapted for administration to the subject by the desired route ofadministration. For example, dosage forms include those adapted for (1)oral administration such as tablets, capsules, caplets, pills, troches,powders, syrups, elixirs, suspensions, solutions, emulsions, sachets,and cachets; and (2) parenteral administration such as sterilesolutions, suspensions, and powders for reconstitution. Suitablepharmaceutically acceptable excipients will vary depending upon theparticular dosage form chosen. In addition, suitable pharmaceuticallyacceptable excipients may be chosen for a particular function that theymay serve in the composition. For example, certain pharmaceuticallyacceptable excipients may be chosen for their ability to facilitate theproduction of uniform dosage forms. Certain pharmaceutically acceptableexcipients may be chosen for their ability to facilitate the productionof stable dosage forms. Certain pharmaceutically acceptable excipientsmay be chosen for their ability to facilitate the carrying ortransporting of the compound or compounds of the invention, onceadministered to the subject, from one organ or portion of the body toanother organ or another portion of the body. Certain pharmaceuticallyacceptable excipients may be chosen for their ability to enhance patientcompliance.

Suitable pharmaceutically acceptable excipients include the followingtypes of excipients: diluents, lubricants, binders, disintegrants,fillers, glidants, granulating agents, coating agents, wetting agents,solvents, co-solvents, suspending agents, emulsifiers, sweeteners,flavoring agents, flavor masking agents, coloring agents, anti-cakingagents, humectants, chelating agents, plasticizers, viscosity increasingagents, antioxidants, preservatives, stabilizers, surfactants, andbuffering agents.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically acceptable carriers andexcipients in appropriate amounts for the use in the invention. Inaddition, there are a number of resources available to the skilledartisan, which describe pharmaceutically acceptable carriers andexcipients and may be useful in selecting suitable pharmaceuticallyacceptable carriers and excipients. Examples include Remington'sPharmaceutical Sciences (Mack Publishing Company), The Handbook ofPharmaceutical Additives (Gower Publishing Limited), and The Handbook ofPharmaceutical Excipients (the American Pharmaceutical Association andthe Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared usingtechniques and methods known to those skilled in the art. Some methodscommonly used in the art are described in Remington's PharmaceuticalSciences (Mack Publishing Company).

In one aspect, the invention is directed to a solid oral dosage formsuch as a tablet or capsule comprising a therapeutically effectiveamount of a compound of the invention and a diluent or filler. Suitablediluents and fillers include lactose, sucrose, dextrose, mannitol,sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinizedstarch), cellulose and its derivatives, (e.g. microcrystallinecellulose), calcium sulfate, and dibasic calcium phosphate. The oralsolid dosage form may further comprise a binder. Suitable bindersinclude starch (e.g. corn starch, potato starch, and pre-gelatinizedstarch) gelatin, acacia, sodium alginate, alginic acid, tragacanth, guargum, povidone, and cellulose and its derivatives (e.g. microcrystallinecellulose). The oral solid dosage form may further comprise adisintegrant. Suitable disintegrants include crospovidone, sodium starchglycolate, croscarmellose, alginic acid, and sodium carboxymethylcellulose. The oral solid dosage form may further comprise a lubricant.Suitable lubricants include stearic acid, magnesium stearate, calciumstearate, and talc.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The composition can also be prepared to prolong orsustain the release as, for example, by coating or embedding particulatematerial in polymers, wax, or the like.

The compounds of the invention may also be coupled with soluble polymersas targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyrancopolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of theinvention may be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example polylactic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels.

In another aspect, the invention is directed to a liquid oral dosageform. Oral liquids such as solution, syrups and elixirs can be preparedin dosage unit form so that a given quantity contains a predeterminedamount of a compound of the invention. Syrups can be prepared bydissolving the compound of the invention in a suitably flavored aqueoussolution; while elixirs are prepared through the use of a non-toxicalcoholic vehicle. Suspensions can be formulated by dispersing thecompound of the invention in a non-toxic vehicle. Solubilizers andemulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylenesorbitol ethers, preservatives, flavor additives such as peppermint oilor other natural sweeteners or saccharin or other artificial sweetenersand the like can also be added.

In another aspect, the invention is directed to parenteraladministration. Pharmaceutical compositions adapted for parenteraladministration include aqueous and non-aqueous sterile injectionsolutions which may contain anti-oxidants, buffers, bacteriostats andsolutes which render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Thecompositions may be presented in unit-dose or multi-dose containers, forexample sealed ampoules and vials, and may be stored in a freeze dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example water for injections, immediately prior touse. Extemporaneous injection solutions and suspensions may be preparedfrom sterile powders, granules and tablets.

Combinations

The compound of the present invention may be administered eithersimultaneously with, or before or after, one or more other therapeuticagent(s). The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the other agent(s).

In one embodiment, the invention provides a product comprising acompound of formula (I) and at least one other therapeutic agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a disease ordisorder associated with a mutant form of IDH. Products provided as acombined preparation include a composition comprising the compound offormula (I) and the other therapeutic agent(s) together in the samepharmaceutical composition, or the compound of formula (I) and the othertherapeutic agent(s) in separate form, e.g. in the form of a kit.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) and another therapeutic agent(s).Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable excipient, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of formula (I). In one embodiment, the kit comprises means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic agent may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent.

Accordingly, the invention provides the use of a compound of formula (I)for treating a disease or disorder associated with a mutant form of IDH,wherein the medicament is prepared for administration with anothertherapeutic agent. The invention also provides the use of anothertherapeutic agent for treating a disease or disorder associated with amutant form of IDH, wherein the medicament is administered with acompound of formula (I).

The invention also provides a compound of formula (I) for use in amethod of treating a disease or disorder associated with a mutant formof IDH, wherein the compound of formula (I) is prepared foradministration with another therapeutic agent. The invention alsoprovides another therapeutic agent for use in a method of treating adisease or disorder associated with a mutant form of IDH, wherein theother therapeutic agent is prepared for administration with a compoundof formula (I). The invention also provides a compound of formula (I)for use in a method of treating a disease or disorder associated with amutant form of IDH, wherein the compound of formula (I) is administeredwith another therapeutic agent. The invention also provides anothertherapeutic agent for use in a method of treating a disease or disorderassociated with a mutant form of IDH, wherein the other therapeuticagent is administered with a compound of formula (I).

The invention also provides the use of a compound of formula (I) fortreating a disease or disorder associated with a mutant form of IDH,wherein the patient has previously (e.g. within 24 hours) been treatedwith another therapeutic agent. The invention also provides the use ofanother therapeutic agent for treating a disease or disorder associatedwith a mutant form of IDH, wherein the patient has previously (e.g.within 24 hours) been treated with a compound of formula (I).

In one embodiment, the other therapeutic agent is selected from:vascular endothelial growth factor (VEGF) receptor inhibitors,topoisomerase II inhibitors, smoothened inhibitors, alkylating agents,anti-tumor antibiotics, anti-metabolites, retinoids, and other cytotoxicagents.

Examples of vascular endothelial growth factor (VEGF) receptorinhibitors include, but are not limited to, bevacizumab (sold under thetrademark Avastin® by Genentech/Roche), axitinib,(N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide,also known as AG013736, and described in PCT Publication No. WO01/002369), Brivanib Alaninate((S)—((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate,also known as BMS-582664), motesanib(N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide,and described in PCT Publication No. WO 02/066470), pasireotide (alsoknown as SOM230, and described in PCT Publication No. WO 02/010192), andsorafenib (sold under the tradename Nexavar®).

Examples of topoisomerase II inhibitors, include but are not limited to,etoposide (also known as VP-16 and Etoposide phosphate, sold under thetradenames Toposar®, VePesid® and Etopophos®), and teniposide (alsoknown as VM-26, sold under the tradename Vumon®).

Examples of alkylating agents, include but are not limited to,temozolomide (sold under the tradenames Temodar® and Temodal® bySchering-Plough/Merck), dactinomycin (also known as actinomycin-D andsold under the tradename Cosmegen®), melphalan (also known as L-PAM,L-sarcolysin, and phenylalanine mustard, sold under the tradenameAlkeran®), altretamine (also known as hexamethylmelamine (HMM), soldunder the tradename Hexalen®), carmustine (sold under the tradenameBiCNU®), bendamustine (sold under the tradename Treanda®), busulfan(sold under the tradenames Busulfex® and Myleran®), carboplatin (soldunder the tradename Paraplatin®), lomustine (also known as CCNU, soldunder the tradename CeeNU®), cisplatin (also known as CDDP, sold underthe tradenames Platinol® and Platinol®-AQ), chlorambucil (sold under thetradename Leukeran®), cyclophosphamide (sold under the tradenamesCytoxan® and Neosar®), dacarbazine (also known as DTIC, DIC andimidazole carboxamide, sold under the tradename DTIC-Dome®), altretamine(also known as hexamethylmelamine (HMM) sold under the tradenameHexalen®), ifosfamide (sold under the tradename Ifex®), procarbazine(sold under the tradename Matulane®), mechlorethamine (also known asnitrogen mustard, mustine and mechloroethamine hydrochloride, sold underthe tradename Mustargen®), streptozocin (sold under the tradenameZanosar®), thiotepa (also known as thiophosphoramide, TESPA and TSPA,and sold under the tradename Thioplex®.

Examples of anti-tumor antibiotics include, but are not limited to,doxorubicin (sold under the tradenames Adriamycin® and Rubex®),bleomycin (sold under the tradename Ienoxane®), daunorubicin (also knownas dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride,sold under the tradename Cerubidine®), daunorubicin liposomal(daunorubicin citrate liposome, sold under the tradename DaunoXome®),mitoxantrone (also known as DHAD, sold under the tradename Novantrone®),epirubicin (sold under the tradename Ellence™), idarubicin (sold underthe tradenames Idamycin®, Idamycin PFS®), and mitomycin C (sold underthe tradename Mutamycin®).

Examples of anti-metabolites include, but are not limited to, claribine(2-chlorodeoxyadenosine, sold under the tradename Ieustatin®),5-fluorouracil (sold under the tradename Adrucil®), 6-thioguanine (soldunder the tradename Purinethol®), pemetrexed (sold under the tradenameAlimta®), cytarabine (also known as arabinosylcytosine (Ara-C), soldunder the tradename Cytosar-U®), cytarabine liposomal (also known asLiposomal Ara-C, sold under the tradename DepoCyt™), decitabine (soldunder the tradename Dacogen®), hydroxyurea (sold under the tradenamesHydrea®, Droxia™ and Mylocel™), fludarabine (sold under the tradenameFludara®), floxuridine (sold under the tradename FUDR®), cladribine(also known as 2-chlorodeoxyadenosine (2-CdA) sold under the tradenameLeustatin™), methotrexate (also known as amethopterin, methotrexatesodim (MTX), sold under the tradenames Rheumatrex® and Trexall™), andpentostatin (sold under the tradename Nipent®).

Examples of retinoids include, but are not limited to, alitretinoin(sold under the tradename Panretin®), tretinoin (all-trans retinoicacid, also known as ATRA, sold under the tradename Vesanoid®),Isotretinoin (13-cis-retinoic acid, sold under the tradenames Accutane®,Amnesteem®, Claravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane®,Isotret®, and Sotret®), and bexarotene (sold under the tradenameTargretin®).

Examples of other cytotoxic agents include, but are not limited to,arsenic trioxide (sold under the tradename Trisenox®), asparaginase(also known as L-asparaginase, and Erwinia L-asparaginase, sold underthe tradenames Elspar® and Kidrolase®).

Intermediates and Examples

The following examples are intended to be illustrative only and notlimiting in any way. Unless otherwise noted, the following Intermediatesand Examples were purified vial silica gel column chromatograph usingRediSep® Rf columns from Teledyne Isco, Inc. Abbreviations used arethose conventional in the art or the following:

ACN acetonitrileBINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthylBSA bovine serum albumin

C Celsius

d doubletdd doublet of doubletsDAST diethylaminosulfur trifluorideDEAD diethyl azodicarboxylate

DIPEA NN-diisopropylethylamine DMF N,N-dimethylformamide

DMSO dimethylsulfoxideDTT dithiothreitolEtOAc ethyl acetateEtOH ethanolg gramh hour(s)hr hour(s)HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphateHEPES 4-(2-hydroxyethyl)-1-piperazineethylanesulfonic acidHPLC high pressure liquid chromatographyIPA isopropyl alcoholkg kilogramL literLC liquid chromatography LCMS liquid chromatography and massspectrometryMeOH methanolMS mass spectrometrym multipletmin minutesmL milliliter(s)μM micromolarm/z mass to charge rationm nanometernM nanomolarN normalNADPH nicotinamide adenine dinucleotide phosphate

NMP N-methylpyrrolidone

NMR nuclear magnetic resonancePdCl₂(dppf).CH₂Cl₂1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complexpsi pounds per square inchrac racemicRt retention times singletsat. saturatedSFC supercritical fluid chromatographyt triplettR rentention timeTCEP tris(2-carboxyethyl)phosphineTEA triethylamineTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin layer chromatography

Instrumentation LCMS:

Unless otherwise noted, LCMS data (also reported herein as simply MS)were recorded using a Waters System (Acuity UPLC and a Micromass ZQ massspectrometer; Column: Acuity HSS C18 1.8-micron, 2.1×50 mm; gradient:5-95% acetonitrile in water with 0.05% TFA over a 1.8 min period; flowrate 1.2 mL/min; molecular weight range 200-1500; cone Voltage 20 V;column temperature 50° C.). All masses reported are those of theprotonated parent ions unless recorded otherwise.

High Resolution Mass Spectrometry (HRMS):

HRMS Method A: ESI-MS data were recorded using a Synapt G2 HDMS (TOFmass spectrometer, Waters) with electrospray ionization source. Theresolution of the MS system was approximately 15000. Leucine Enkephalinwas used as lock mass (internal standards) infused from lockspary probe.The compound was infused into the mass spectrometer by UPLC (Acquity,Waters) from sample probe. The separation was performed on Acquity UPLCBEH C18 1×50 mm column at 0.2 mL/min flow rate with the gradient from 5%to 95% in 3 min. Solvent A was Water with 0.1% Formic Acid and solvent Bwas Acetonitrile with 0.1% Formic Acid. The mass accuracy of the systemhas been found to be <5 ppm with lock mass.

HRMS Method B: LC-MS/ESI-MS data were recorded on an Acquity G2 XevoQTof—Rs(FWHM)>20000 Accuracy<5 ppm. The separation was performed onAcquity CSH 1.7 μm 2.1×50 mm—50° C. column Eluent A: Water+3.75 mMammonium acetate. Eluent B: Acetonitrile. Gradient: from 2 to 98% B in4.4 min—flow 1.0 mL/min.

HRMS Method C: Same as HRMS method B, except Gradient: from 40 to 98% Bin 3.4 min—flow 1.0 mL/min.

HRMS Method D: LC-MS/ESI-MS data were recorded on an Acquity LCTpTof—Rs(FWHM)>12000<5 ppm. The separation was performed on Acquity BEHC181.7 μm 2.1×50 mm—50° C. column Eluent A: Water+0.1% Formic Acid+3.75 mMAm acetate. Eluent B: Acetonitrile+0.04% formic+3.75 mM Am Acetate+5%Water. Gradient: from 0.2 to 98% B in 4.4 min—flow 1.0 mL/min.

HRMS methods A, B, C and D are referred to throughout as HRMS(A),HRMS(B), HRMS(C) and HRMS(D) respectively.

INTERMEDIATES Intermediate 1: benzyl((2R)-(3R)-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate

A solution of(S)-2-(((benzyloxy)carbonyl)amino)-(R)-3-(tert-butoxy)butanoic aciddicyclohexylammonium salt (500 mg, 1.0 mmol) in 10 ml of THF andisobutyl chloroformate (167 mg, 1.2 mmol, 1.2 equiv) at −25° C. wasadded N-methylmorpholine (124 mg, 1.2 mmol, 1.2 equiv), the mixture wasstirred at same temperature for 10 min and filtered. The filtrate wascooled to −20° C. and to it was added NaBH₄, followed by 2 ml of waterimmediately afterwards. The reaction mixture was stirred at sametemperature for 5 min. then gradually warmed to room temperature for 25min, poured into water (10 ml) and extracted with EA (2×20 ml). Thecombined organic phases were washed with water, brine and dried overNa₂SO₄. The solvent was removed to yield the desired product as theclear oil. No further purification was required for next step. ¹H NMR(400 MHz, CDCl₃) δ 7.37-7.16 (m, 5H), 5.25 (d, J=8.0 Hz, 1H), 5.02 (s,1H), 4.04 (ddd, J=12.0, 8.9, 2.8 Hz, 1H), 3.92-3.75 (m, 1H), 3.59 (dddd,J=32.3, 14.6, 8.2, 4.3 Hz, 2H), 1.10 (s, 9H), 1.09-1.06 (m, 3H).

Intermediate 2: (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one

Method A: A solution of benzyl((2R)-(3R)-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (134 mg, 0.45mmol in 5 mL of THF) was pre-cooled to 0° C.) under nitrogen was treatedwith potassium tert-butoxide (153 mg, 1.4 mmol, 3.0 equiv), it wasstirred at same temperature for 2 hours, 5 mL of water was added, it wasextracted with EtOAc (2×20 mL), the combined organic layers were washedwith water, brine, dried over Na₂SO₄, the solvent was removed to yieldthe desired product as a yellow oil, no further purification wasrequired for next step. ¹H NMR (400 MHz, CDCl₃) δ 6.20 (br s, 1H), 4.33(t, J=8.7 Hz, 1H), 4.07 (dd, J=8.9, 5.5 Hz, 1H), 3.67-3.58 (m, 1H),3.58-3.49 (m, 1H), 1.13 (s, 9H), 1.02 (d, J=6.0 Hz, 3H).

Method B: (2R,3R)-2-amino-3-(tert-butoxy)butan-1-ol hydrochloride (19.77g, 100 mmol) was dissolved in DCM (200 mL) at 0° C., and addedtriethylamine (69.7 ml, 500 mmol). Solution was treated over 90 minswith a solution of triphosgene (12.76 g, 43.0 mmol) in DCM (100 mL)[keep the reaction mixture below 5° C.]. The reaction mixture wasstirred at 0° C. for 30 mins before allowing to warm to room temperatureand stirring overnight. The reaction mixture was treated with aqueoussaturated NH4Cl (200 mL), water (50 mL) and stirred vigorously at roomtemperature for 1 h. Separated the organics, extracted the aqueous withDCM (500 mL), combined the organics and washed them with 1N HCl (3×150mL), and aqueous saturated NH4Cl, dried (MgSO4) and concentrated todryness (careful not to leave under vacuum or heat excessively) to givea pale brown oil. TLC shows mostly product with some small by-productpeaks at higher Rf and some baseline materials. Subjected to flashcolumn chromatography on silica with neat heptanes, 20% Et2O/heptanes,50% Et2O/heptanes, neat Et2O, and 30% EtOAc/Et2O. TLC:neat ether, stainwith cupric ammonium sulfate (heat hard for 1 minute to see the blueproduct stain); product Rf=0.34. Product off mostly with neat Et2O. Oneof the cleanest single fractions was concentrated to dryness to give2.02 g of a very pale yellow/brown oil which crystallized upon standing.The remainder of the product fractions were combined and concentrated todryness to give 15.2 g as a pale brown oil, which was seeded withcrystals of the initial batch to give a pale brown crystalline solid.Overall yield ˜90%. ¹H NMR (400 MHz, CDCl₃) δ 5.28 (br s, 1H); 4.44 (t,1H); 4.13-4.09 (m, 1H); 3.7-3.57 (m, 2H); 1.23 (s, 9H); 1.11 (d, 3H).

Intermediate 3:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one

Method A: A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one(86 mg, 0.46 mmol) and 2,4-difluoropyrimidine (79 mg, 0.55 mmol, 1.2equiv) in 3 ml of DMF was cooled to 0° C. under N2 before adding NaH(60%, 28 mg, 0.69 mmol, 1.5 equiv) slowly. The reaction mixture wasstirred at 0° C. for 45 min., then gradually warmed to room temperature,and stirred at room temperature overnight. The reaction was quenchedwith 5 ml of water, and extracted with EtOAc (2×10 ml). The solvent wasremoved to yield the crude product. Silica gel column chromatography(ethyl acetate in heptane 10 to 50%) provided the desired product as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (dd, J=5.8, 2.1 Hz, 1H),8.14 (dd, J=5.8, 3.8 Hz, 1H), 4.85-4.63 (m, 2H), 4.56-4.30 (m, 2H), 1.26(s, 9H), 1.05 (d, J=6.5 Hz, 3H).

Method B: A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one(5 g, 26.7 mmol) in DMF (50 mL) was cooled to −5° C. under N2atmosphere. Internal temperature was monitored and maintained at ca. −5°C. during the portionwise addition of 60% NaH (1.602 g, 40.1 mmol) over5 mins (no appreciable exotherm seen, but effervescence observed andcloudy suspension resulted). Added 2,4-difluoropyrimidine (2.507 mL,29.4 mmol) dropwise whilst still maintaining the temperature at ca. −5°C. After complete addition the reaction mixture was stirred at thistemperature for 15 mins before removing the cooling bath and allowingthe reaction mixture to warm to room temperature (ca. 27° C. internaltemp). Left stirring at room temperature for 2 h. Workup: [Safety Note:NaF salt present. Do not acidify workup] Quenched the reaction mixturewith water (100 mL) which resulted in considerable effervescencealthough minimal increase in temperature. Added EtOAc (75 mL) andseparated, extracted the aqueous with EtOAc (2×75 mL), combined theorganics, washed with water (100 mL), brine (50 mL), dried (MgSO4) andconcentrated to dryness to give crude product as a pale yellow oil [8.33g] which was purified by silica gel chromatography (initial rampDCM/heptane 5 to 100%, then EtOAc/DCM 0% to 20%, product off with ˜5%EtOAc/DCM). Combined and concentrated the pure product fractions todryness to give a white solid which was placed under high vacuum for 4h. ¹H NMR (400 MHz, CDCl₃) δ 8.5 (dd, 1H), 8.15 (dd, 1H); 4.77-4.66 (m,2H); 4.53-4.42 (m, 2H); 1.26 (s, 9H); 1.05 (d, 3H). MS m/z 284.1 (M+H)+.

Intermediate 4:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one

A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (5 g,26.7 mmol) in DMF (50 mL) was cooled to −5° C. under N2 atmosphere.Internal temperature was monitored and maintained at ca. −5° C. duringthe portionwise addition of 60% NaH (1.28 g, 32 mmol) over 5 mins (noappreciable exotherm seen, but effervescence observed and cloudysuspension resulted). Added 2,4,5-trifluoropyrimidine (3.76 g, 28 mmol)dropwise whilst still maintaining the temperature at ca. −5° C. Aftercomplete addition the reaction mixture was stirred at this temperaturefor 15 mins before removing the cooling bath and allowing the rm to warmto room temperature (ca. 27° C. internal temp). Left stirring at roomtemperature for 6 h. Sampled reaction mixture and quenched with water,extracted into EtOAc; TLC and LCMS show significant product butremaining oxazolidinone sm. Cooled reaction mixture to 0° C. and addedan additional portion of trifluoropyrimidine (1.2 g, 8.95 mmol), warmedto room temperature and left stirring for 3 h at rt. Still faintresidual sm seen by TLC of sample, but quenched reaction mixture at thispoint. Workup: [Safety Note: NaF salt present. Do not acidify workup]Quenched the reaction mixture with water (100 mL) which resulted inconsiderable effervescence. Added EtOAc (75 mL) and separated, extractedthe aqueous with EtOAc (2×75 mL), combined the organics, washed withwater (100 mL), brine (50 mL), dried (MgSO4) and concentrated to drynessto give crude product as a pale yellow oil. Crude was purified by silicagel chromatography (initial neat DCM, then ramp to 20% EtOAc/DCM). Pureproduct fractions were combined and concentrated to dryness to give acolourless oil which was placed under high vacuum. Upon standing the oilconverted into a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (dd, J=3, 1Hz, 1H); 4.73-4.68 (m, 1H); 4.62-4.52 (m, 2H); 4.34-4.28 (m, 1H); 1.20(s, 9H); 1.11 (d, 3H). MS m/z 302.1 (M+H)+.

Intermediate 5:(R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

A solution of(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(1.0 g, 3.35 mmol) in 20 ml of DCM was cooled in an ice bath, andtreated with 8.16 mL of TFA. The mixture was stirred at same temperaturefor 4 hours, and allowed to warm to room temp and stir 16 h. Thereaction was poured into 10 mL water. The DCM was removed in vacuo. Theaqueous was basified by slow addition of saturated NaHCO3 solution, thenextracted with (2×30 mL) EtOAc. The organics were washed with 30 mLbrine, and dried over Na2SO4. Filtered and concentrated to give thedesired alcohol,(R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one(0.56 g, 70% yield) as a white solid. HRMS(B) tR=0.80 min; MS m/z 228.4(M+H)+.

Intermediate 6: (R)-methyl3-(2-fluoropyrimidin-4-yl)-2-oxooxazolidine-4-carboxylate

A solution of (R)-methyl 2-oxooxazolidine-4-carboxylate (200 mg, 1.4mmol) and 2,4-fluoropyrimidine (176 mg, 1.5 mmol, 1.1 equiv) in DMF (3mL) was treated with NaH (60%, 66.2 mg, 1.2 mmol, 1.2 equiv), then theresulting mixture was stirred at 0° C. for 45 minutes, then roomtemperature for 12 h. The reaction mixture was diluted with EtOAc (20mL), washed with sat. NH₄Cl (15 mL) and 4% aqueous NaCl (2×100 mL),dried over Na₂SO₄, filtered and concentrated. Silica gel columnchromatography (EtOAc/Heptane 10% to 50%) to provide

(R)-methyl 3-(2-fluoropyrimidin-4-yl)-2-oxooxazolidine-4-carboxylate(240 mg, white waxy solid) in 71% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.47(dd, J=5.8, 2.0 Hz, 1H), 8.07 (dd, J=5.7, 3.7 Hz, 1H), 5.18 (dd, J=9.4,3.7 Hz, 1H), 4.68 (t, J=9.4 Hz, 1H), 4.45 (dd, J=9.3, 3.7 Hz, 1H), 3.78(s, 3H).

Intermediate 7: 2-amino-4,4,4-trifluoro-3-methylbutan-1-ol

To a chilled (0° C.) solution of2-amino-4,4,4-trifluoro-3-methylbutanoic acid (736 mg, 4.30 mmol) in THF(9 mL) was added aluminum (Ill) lithium hydride (2.26 mL, 9.03 mmol, 4M)dropwise. After addition complete, the reaction was allowed to stir atambient temperature for 1 hour. Cool to 0° C. and quench w/sat. Na₂SO₄soln, added EtOAc (50 mL), Na₂SO₄, filtered, conc. in vacuo affordedmaterial that was a mixture of the title compound and the startingmaterial acid in a 3:2 ratio which was used crude in the next step. ¹HNMR (400 MHz, CDCl₃) δ 3.71 (dd, J=10.7, 3.7 Hz, 1H), 3.57 (dd, J=10.4,5.2 Hz, 1H), 3.45 (ddd, J=10.7, 8.0, 4.8 Hz, 2H), 3.28 (ddd, J=8.2, 5.3,2.9 Hz, 1H), 3.06 (td, J=7.3, 3.6 Hz, 1H), 2.44-2.20 (m, 2H), 2.04-1.54(m, 1H), 1.21-1.08 (m, 7H). ¹⁹F NMR (376 MHz, CDCl₃) δ −68.33 (s),−70.12 (s).

Intermediate 8: 4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one

To a solution of 2-amino-4,4,4-trifluoro-3-methylbutan-1-ol (580 mg,3.69 mmol) in DCM (13 ml) was added triethylamine (1.132 ml, 8.12 mmol)and added dropwise a solution of triphosgene (329 mg, 1.107 mmol) in 1mL in DCM (3 ml) over 10 min. The reaction mixture was washed with sat.NH₄Cl solution (13 ml) dry, and concentated in vacuo. Afforded 450 mg(It yellow solid). Used crude in the next step. ¹H NMR (400 MHz, CDCl₃)δ 5.91 (d, J=13.3 Hz, 1H), 4.61-4.34 (m, 1H), 4.22-4.00 (m, 2H), 3.05(q, J=7.3 Hz, 1H), 2.54-2.14 (m, 1H), 1.34 (t, J=7.3 Hz, 1H), 1.17 (d,J=7.1 Hz, 2H), 1.09 (d, J=7.1 Hz, 1H). MS 183.0507 m/z.

Intermediate 9:3-(2-fluoropyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one

A solution of 4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one (270 mg,1.474 mmol) and 2,4-difluoropyrimidine (171 mg, 1.474 mmol, 1 eq) in DMF(4 mL) was treated with NaH (60%, 88 mg, 2.212 mmol, 1.5 eq), then theresulting mixture was stirred at 0° C. for 10 minutes, then roomtemperature for 1 h. The reaction mixture was quenched with sat. Na₂SO₄(15 mL) diluted with EtOAc (20 mL), washed and 4% aqueous NaCl (3×20mL), dried over Na₂SO₄, concentrated in vacuo. Flash columnchromatography (silica, 120 g, 15 m) 5% EtOAc/DCM to provide3-(2-fluoropyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one(100 mg, white solid). ¹H NMR (400 MHz, CDCl₃) δ 8.55 (dd, J=5.8, 2.1Hz, 1H), 8.20 (dd, J=5.8, 3.7 Hz, 1H), 5.04-4.84 (m, 1H), 4.68 (dd,J=9.5, 2.6 Hz, 1H), 4.54 (t, J=9.2 Hz, 1H), 3.34 (ddddd, J=13.3, 9.3,7.1, 3.9, 1.6 Hz, 1H), 1.29 (d, J=7.3 Hz, 3H). MS 279.0631 m/z.

Intermediate 10:(R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one

Step 1

To a round bottom flask was added NaH (0.54 g, 13.5 mmol, 57% despersionin mineral oil) to a solution of 2,4,6-trichloropyrimidine (1.22 ml,10.6 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (1.8 g,9.61 mmol) in DMF (32 mL) at 0° C. (ice bath) under a bubbler. Theyellow suspension was then stirred at 0° C. for 15 min and then the icebath was removed and reaction mixture allowed to stir 1 hr at roomtemperature. Reaction mixture was diluted with EtOAc and then carefullyquenched with brine. The layers were separated and the aqueous layer wasextracted with EtOAc. The combined organic layeres were dried (Na₂SO₄),filtered and concentrated onto silica gel. Silica gel columnchromatography (EtOAc/Heptane 0 to 100%) provided(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one(2.1 g, 6.28 mmol, 65% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃)δ 1.04 (d, J=6.55 Hz, 3H) 1.26 (s, 9H) 4.38-4.48 (m, 2H) 4.64-4.75 (m,2H) 8.22 (s, 1H). LCMS m/z 334.1 (M+H)⁺, Rt 1.10 min.

Step 2

To a round bottom flask containing(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one(1 g, 2.99 mmol) was added DCM (7.5 mL) followed by the addition of TFA(7.5 mL). The resulting homogenous reaction mixture allowed to stir 1 hrat room temperature. The volatiles were then removed. Residue dissolvedin DCM and neutralized with a saturated solution of NaHCO₃. The phaseswere partioned, the aqueous phase extracted with DCM. Organic phasescombined, washed with water, brine, dried (Na₂SO₄), filtered andconcentrated to a white foam of(R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one(737 mg, 2.65 mmol, 89% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.19 (d,J=6.46 Hz, 3H) 4.47 (dd, J=9.37, 8.53 Hz, 1H) 4.55 (quin, J=5.69 Hz, 1H)4.63 (dd, J=9.49, 2.79 Hz, 1H) 4.89 (ddd, J=8.19, 4.96, 2.79 Hz, 1H)8.24 (s, 1H). LCMS m/z 278.0 (M+H)⁺, Rt 0.66 min.

Step 3

To a round bottom flask was added(R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one(364 mg, 1.31 mmol) followed by the addition of DCM (10.8 mL). Thereaction mixture was then cooled to 0° C. in a (ice/water bath) undernitrogen. To this cold solution was added tetrafluoroboric acid (0.20mL, 1.31 mmol, 50% aqueous solution) followed by the addition oftrimethylsilyldiazomethane (1.96 mL, 3.93 mmol, 2 M in hexanes) dividedinto 3 portions added 20 min apart. A second addition oftrimethylsilyldiazomethane in hexanes (1.96 mL, 3.93 mmol, 2 M inhexanes) again divided into 3 portions added 20 min apart was added.Reaction mixture was quenched with water and diluted with DCM. Phasespartitioned and the aqueous phase extracted with DCM. Organic phasescombined and washed with brine, dried (Na₂SO₄), filtered andconcentrated onto silica gel. Silica gel column chromatography(EtOAc/Heptane 0 to 100%) provided(R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one(119 mg, 0.41 mmol, 31% yield) as a colorless oil which crystallizesupon standing. ¹H NMR (400 MHz, CDCl₃) δ 1.09 (d, J=6.50 Hz, 3H) 3.44(s, 3H) 4.09 (qd, J=6.46, 4.16 Hz, 1H) 4.38-4.49 (m, 1H) 4.60 (dd,J=9.49, 2.84 Hz, 1H) 4.99 (ddd, J=8.50, 3.95, 2.96 Hz, 1H) 8.23 (s, 1H).LCMS m/z 292.0 (M+H)⁺, Rt 0.86 min.

Intermediate 11:(R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one

Step 1

To a round bottom flask containing a stir bar and(2S,3R)-2-((tert-butoxycarbonyl)amino)-3-methoxybutanoic acid (2.5 g,10.7 mmol) in THF (80 mL) under nitrogen was cooled to −30° C. in a dryice/acetone bath. To this cold solution was added isobutyl chloroformate(1.7 mL, 12.9 mmol) followed by the addition of N-methylmorpholine (1.4mL, 12.9 mmol). Mixture was stirred for 15 min at −30° C.N-Methylmorpholine salt develops and was filtered from mixture. Motherliquor was cooled to −30° C. where upon sodium borohydride (0.61 g, 16.1mmol) was added followed by the addition of water (10 mL) immediatelyafterwards. Reaction mixture allowed to stir for 15 min at −20° C. thengradually allowed to warm to room temperature. Reaction mixture wasstirred for 30 min at room temperature. Reaction mixture was thendiluted with water and extracted with EtOAc. Organic phases combined,washed with water, brine, dried (Na₂SO₄), filtered and concentrated toafford tert-butyl ((2R,3R)-1-hydroxy-3-methoxybutan-2-yl)carbamate (2.0g, 9.1 mmol, 85% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ1.18 (d, J=6.26 Hz, 3H) 1.45 (s, 9H) 3.33 (s, 3H) 3.55-3.84 (m, 4H).LCMS m/z 220.2 (M+H)⁺, Rt 0.57 min.

Step 2

To a round bottom flask containing tert-butyl((2R,3R)-1-hydroxy-3-methoxybutan-2-yl) (2 g, 9.1 mmol) and stir bar wasadded DCM (5.0 mL) followed by the addition of TFA (5.0 mL). Resultingreaction mixture allowed to stir 30 min at room temperature. Volatileswere removed to afford (2R,3R)-2-amino-3-methoxybutan-1-ol (2.1 g, 9.0mmol, 99% yield) as a TFA salt. Material was used in next step withoutfurther purification. LCMS m/z 120.0 (M+H)⁺, Rt 0.15 min.

Step 3

To a round bottom flask containing (2R,3R)-2-amino-3-methoxybutan-1-ol(2.1 g, 9.0 mmol) and a stir bar was added acetonitrile (100 mL)followed by the addition of 2,4-dichloropyrimidine (1.34 g, 9.0 mmol)and DIEA (4.7 mL, 27.0 mmol). Resulting reaction mixture allowed to stir18 hr at room temperature. Volatiles were then removed. Residue waspartitioned between EtOAc and water. Aqueous layer extracted with EtOAc.Organic phases combined, washed with water, brine, dried (Na₂SO₄),filtered and concentrated to afford(2R,3R)-2-((2-chloropyrimidin-4-yl)amino)-3-methoxybutan-1-ol (1.68 g,3.63 mmol, 40% yield) which contains some unreacted2,4-dichloropyrimidine. LCMS m/z 232.0 (M+H)⁺, Rt 0.38 min.

Step 4

To a round bottom flask containing(2R,3R)-2-((2-chloropyrimidin-4-yl)amino)-3-methoxybutan-1-ol (1.68 g,3.63 mmol) and a stir bar under nitrogen was added DCM (18 mL). Theresulting reaction mixture cooled to 0° C. in a brine/ice bath. To thiscold solution was then added triphosgene (0.59 g, 1.99 mmol) followed bythe addition of 2,6-dimethylpyridine (2 mL, 17.0 mmol). Resultingreaction mixture allowed to stir 30 min at 0° C. The reaction mixturewas diluted with DCM and water and allowed to stir 1 hr at roomtemperature. The phases partitioned and the aqueous phase extracted withDCM. Organic phases were combined, washed with water, brine, dried(Na₂SO₄), filtered and concentrated onto silica gel. Silica gel columnchromatography (EtOAc/Heptane 0 to 100%) provided(R)-3-(2-chloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one(145 mg, 0.56 mmol, 15% yield) as a white crystalline. ¹H NMR (400 MHz,CDCl₃) δ 1.09 (d, J=6.26 Hz, 3H) 3.45 (s, 3H) 4.15 (qd, J=6.39, 4.30 Hz,1H) 4.39-4.47 (m, 1H) 4.60 (dd, J=9.39, 2.74 Hz, 1H) 5.02 (dt, J=8.61,3.52 Hz, 1H) 8.17 (d, J=5.87 Hz, 1H) 8.48 (d, J=5.87 Hz, 1H). LCMS m/z258.1 (M+H)⁺, Rt 0.69 min.

Step 5

To a microwe vial with stir bar was added(R)-3-(2-chloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one(145 mg, 0.56 mmol), potassium fluoride (327 mg, 5.63 mmol) and DMSO (4mL). Vial capped and heated to 120° C. in a sand bath for 3 hr. Reactionmixture was then cooled to room temperature, diluted with water andaqueous mixture extracted with EtOAc. The Organic phases were combinedand washed with water, brine, dried (Na₂SO₄), filtered and concentratedto afford a white crystalline of(R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one(117 mg, 0.49 mmol, 86% yield). LCMS m/z 242.1 (M+H)⁺, Rt 0.63 min.

Intermediate 12:(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one

Step 1

To a round bottom flask containing a stir bar and(2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(tert-butoxy)butanoicacid (8.55 g, 21.5 mmol) in THF (72 mL) under nitrogen was cooled to−30° C. in a dry ice/acetonitrile bath. To this cold solution was addedisobutyl chloroformate (3.4 mL, 25.8 mmol) followed by the addition ofN-methylmorpholine (2.8 mL, 25.8 mmol). Mixture was stirred for 15 minat −30° C. N-Methylmorpholine salt develops and was filtered frommixture. Mother liquor was cooled to −30° C. where upon sodiumborohydride (1.22 g, 32.3 mmol) was added followed by the addition ofwater (25 mL) immediately afterwards. Reaction mixture allowed to stirfor 15 min at −20° C. then gradually allowed to warm to roomtemperature. Reaction mixture was stirred for 30 min at roomtemperature. Reaction mixture was diluted with water, extracted withEtOAc. Organic phases combined, washed with water, brine, dried(Na₂SO₄), filtered and concentrated to afford (9H-fluoren-9-yl)methyl((2R,3S)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (8.11 g, 21.15mmol, 98% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 1.18 (s,9H) 1.24 (d, J=5.87 Hz, 3H) 4.11-4.26 (m, 2H) 4.42 (d, J=7.04 Hz, 2H)5.73 (d, J=7.43 Hz, 1H) 7.29-7.35 (m, 2H) 7.38-7.45 (m, 2H) 7.61 (t,J=6.06 Hz, 2H) 7.78 (d, J=7.43 Hz, 2H)). LCMS m/z 384.3 (M+H)⁺, Rt 0.96min.

Step 2

To a round bottom flask with stir bar was added (9H-fluoren-9-yl)methyl((2R,3S)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (4.7 g, 12.3mmol) and acetonitrile (100 mL) followed by the addition of piperidine(1.8 mL, 18.4 mmol). The flask was capped and stirred for 18 hr at roomtemperature. The volatiles were then removed. A white solid developswhich contains the amino alcohol product and the fmoc deprotection byproducts. Solids were redissolved in acetonitrile (50 ml) (some of thefmoc polymer is insoluble) and 2,4-dichloropyrimidine (5.48 g, 36.8mmol) and DIEA (2.141 mL, 12.26 mmol) were added. Resulting reactionmixture allowed to stir 18 hr at room temperature. The volatiles wereagain removed. Reaction mixture was diluted with water and extractedwith EtOAc. Organic phases combined, washed with water, brine, dried(Na₂SO₄), filtered and concentrated onto silica gel. Silica gel columnchromatography (EtOAc/Heptane 0 to 100%) provided(2R,3S)-3-(tert-butoxy)-2-((2-chloropyrimidin-4-yl)amino)butan-1-ol(1.80 g, 6.58 mmol, 54% yield) as a colorless oil which crystallizesupon standing. LCMS m/z 274.1 (M+H)⁺, Rt 0.56 min.

Step 3

To a round bottom flask containing(2R,3S)-3-(tert-butoxy)-2-((2-chloropyrimidin-4-yl)amino)butan-1-ol (1.8g, 6.58 mmol) and a stir bar under nitrogen was added DCM (66 ml). Theresulting reaction mixture cooled to −70° C. in a dry ice/acetone bath.To this cold solution was added triphosgene (1.07 g, 3.62 mmol) followedby the addition of 2,6-dimethylpyridine (3.6 mL, 30.9 mmol). Resultingreaction mixture allowed to gradually warm to room temperature andstirred for 30 min at room temperature. Reaction mixture diluted withDCM and water and allowed to stir 1 hr at room temperature. The phaseswere then partioned and aqueous extracted with DCM. Organics phasescombined, washed with water, brine, dried (Na₂SO₄), filtered andconcentrated onto silica gel. Silica gel column chromatography(EtOAc/Heptane 0 to 100%) provided(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one(1.44 g, 4.80 mmol, 73% yield) as a white crystalline. LCMS m/z 300.1(M+H)⁺, Rt 0.91 min.

Intermediate 13:(R)-4-((R)-1-tert-butoxyethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one

A solution of (R)-4-((R)-1-tert-butoxyethyl)oxazolidin-2-one (0.830 g,4.43 mmol) and 2,4,6-trichloropyrimidine (0.894 g, 4.88 mmol, 1.10equiv) in DMF (15 mL) was treated with NaH (60%, 0.248 g, 6.21 mmol,1.40 equiv), then the resulting mixture (yellow) was stirred at roomtemperature for 1 h. The reaction mixture was diluted with EtOAc (100mL) and quenched with saturated aqueous NaCl (100 mL). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (2×30mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%)provided(R)-4-((R)-1-tert-butoxyethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one(1.0 g, white solid) in 69% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.22 (s,1H), 4.70-4.66 (m, 2H), 4.45-4.40 (m, 2H), 1.26 (s, 9H), 1.04 (d, J=6.6Hz, 3H); MS m/z 334.0 (M+H)⁺; Rt-1.10 min.

Intermediate 14:(R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)oxazolidin-2-one

A solution of (R)-4-((R)-1-tert-butoxyethyl)oxazolidin-2-one (0.100 g,0.534 mmol) and 4-chloro-6-(difluoromethyl)-2-(methylthio)pyrimidine(0.124 g, 0.587 mmol, 1.10 equiv) in DMF (2.7 mL) was treated with NaH(60%, 0.026 g, 0.64 mmol, 1.20 equiv), then the resulting mixture(yellow) was stirred at room temperature for 30 min. The reactionmixture was diluted with EtOAc (20 mL), washed with saturated aqueousNaCl (2×20 mL), dried over Na₂SO₄, filtered and concentrated. Silica gelcolumn chromatography (EtOAc/Heptane 0 to 40%) provided(R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)oxazolidin-2-one(0.164 g, white solid) in 85% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s,1H), 6.45 (t, J=54 Hz, 1H), 4.80-4.72 (m, 1H), 4.66 (dd, J=9.4, 3.0 Hz,1H), 4.49-4.34 (m, 2H), 2.58 (s, 3H), 1.25 (s, 9H), 1.02 (d, J=6.5 Hz,3H); MS m/z 362.3 (M+H)⁺; Rt-1.09 min.

Intermediate 15:(R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylsulfonyl)pyrimidin-4-yl)oxazolidin-2-one

A solution of(R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)oxazolidin-2-one(0.164 g, 0.454 mmol) in DCM (4.5 mL) was treated with m-CPBA (0.244 g,1.09 mmol, 2.4 equiv) at 0° C. The mixture was allowed to warm to roomtemperature and stirred for 4 h. The reaction was carefully quenchedwith a 1:1 mixture of 1 M aqueous sodium thiosulfate solution andsaturated aqueous sodium bicarbonate solution (20 mL). The mixture wasextracted with DCM (3×20 mL) and the combined organic extracts werewashed with saturated aqueous NaCl (20 mL), dried over Na₂SO₄, filteredand concentrated. Silica gel column chromatography (EtOAc/Heptane 20% to40%) provided(R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylsulfonyl)pyrimidin-4-yl)oxazolidin-2-oneas a white solid in 82% yield. MS m/z 338.1 (M+H-tert-butyl)⁺; Rt-0.87min.

Intermediate 16:(R)-4-((R)-1-tert-butoxyethyl)-3-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)oxazolidin-2-one

A solution of (R)-4-((R)-1-tert-butoxyethyl)oxazolidin-2-one (0.070 g,0.374 mmol) and 2,4-dichloro-6-(trifluoromethyl)pyrimidine (0.089 g,0.411 mmol, 1.10 equiv) in DMF (1.3 mL) was treated with NaH (60%, 0.018g, 0.45 mmol, 1.20 equiv), then the resulting mixture (yellow) wasstirred at room temperature for 60 min. The reaction mixture was dilutedwith EtOAc (20 mL), washed with saturated aqueous NaCl (2×20 mL), driedover Na₂SO₄, filtered and concentrated. Silica gel column chromatography(EtOAc/Heptane 0 to 15%) provided(R)-4-((R)-1-tert-butoxyethyl)-3-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)oxazolidin-2-one(0.116 g, white solid) in 84% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s,1H), 4.76 (ddd, J=8.5, 4.2, 2.9 Hz, 1H), 4.70 (dd, J=9.5, 2.9 Hz, 1H),4.50-4.42 (m, 2H), 1.26 (s, 9H), 1.04 (d, J=6.5 Hz, 3H). MS m/z 368.1(M+H)⁺; Rt-1.10 min.

Intermediate 17:(2R,3R)-3-(tert-butoxy)-2-((2-chloro-6-methylpyrimidin-4-yl)amino)butan-1-ol

A solution of (2R,3R)-2-amino-3-(tert-butoxy)butan-1-ol (267 mg, 1.35mmol, 1.1 equiv), 2,4-dichloro-6-methylpyrimidine (200 mg, 1.23 mmol,1.0 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.54 mL, 3.1 mmol,2.5 equiv) in 1,4-dioxane (6 mL) was heated at 75° C. for 4 h. Thereaction was cooled to room temperature and concentrated in vacuo.Silica gel column chromatography (EtOAc/Heptane) provided(2R,3R)-3-(tert-butoxy)-2-((2-chloro-6-methylpyrimidin-4-yl)amino)butan-1-ol(86 mg, white solid) in 24% yield. ¹H NMR (400 MHz, CDCl₃) δ 6.17 (s,1H), 4.02 (m, 2H), 3.79-3.64 (m, 2H), 2.30 (s, 3H), 1.22 (s, 9H), 1.18(d, J=6.2 Hz, 3H); MS m/z 288.1 (M+H)⁺; Rt-0.59 min.

Intermediate 18:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-methylpyrimidin-4-yl)oxazolidin-2-one

Triphosgene (35 mg, 0.12 mmol, 0.4 equiv) was added to a solution of(2R,3R)-3-(tert-butoxy)-2-((2-chloro-6-methylpyrimidin-4-yl)amino)butan-1-ol(86 mg, 0.30 mmol) in DCM (3 mL) at −78° C., followed by the dropwiseaddition of 2,6-lutidine (0.14 mL, 1.2 mmol, 4 equiv). The solution wasallowed to warm to room temperature and was then heated at 35° C. for 5hours. The reaction was then cooled to room temperature and diluted withDCM (30 mL) and saturated aqueous sodium chloride (30 mL). The layerswere separated and the organic layer was dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/Heptane) provided(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-methylpyrimidin-4-yl)oxazolidin-2-one(0.057 g, white solid) in 61% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.01 (s,1H), 4.73 (ddd, J=8.6, 4.1, 3.0 Hz, 1H), 4.65 (dd, J=9.4, 2.9 Hz, 1H),4.48 (m, 1H), 4.41 (m, 1H), 2.52 (s, 3H), 1.26 (s, 9H), 1.03 (d, J=6.5Hz, 3H); MS m/z 314.1 (M+H)⁺; Rt-1.02 min.

Intermediate 19:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoro-6-methylpyrimidin-4-yl)oxazolidin-2-one

Potassium fluoride (0.063 g, 1.08 mmol, 10 equiv) was added to asolution of(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-methylpyrimidin-4-yl)oxazolidin-2-one(34 mg, 0.108 mmol) in DMSO (1.1 mL). The suspension was heated at 120°C. for 3 hours and then cooled to room temperature. The reaction wasdiluted with ethyl acetate (20 mL) and water (20 mL). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (20mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to give crude(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoro-6-methylpyrimidin-4-yl)oxazolidin-2-one,which was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ7.99 (d, J=3.8 Hz, 1H), 4.71 (m, 1H), 4.65 (m, 1H), 4.46 (m, 1H), 4.41(m, 1H), 2.53 (s, 3H), 1.25 (s, 9H), 1.03 (d, J=6.5 Hz, 3H); MS m/z298.2 (M+H)⁺; Rt-0.96 min.

Intermediate 20: methyl6-((R)-4-((R)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-2-chloropyrimidine-4-carboxylate

Sodium hydride (60% dispersion in mineral oil, 23 mg, 0.58 mmol, 1.2equiv) was added to a solution of methyl2,6-dichloropyrimidine-4-carboxylate (100 mg, 0.483 mmol) and(R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (90 mg, 0.483 mmol, 1equiv) in DMF (2.4 mL) at 0° C. The suspension was stirred at 0° C. for1 hour, by which time it turned yellow. The reaction was quenched withdilute aqueous sodium chloride (20 mL) and extracted with ethyl acetate(2×20 mL). The combined extracts were dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/Heptane) separatedthe regioisomers and provided methyl6-((R)-4-((R)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-2-chloropyrimidine-4-carboxylate(0.111 g, white solid) in 64% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.79 (s,1H), 4.76 (m, 1H), 4.69 (dd, J=9.4, 2.7 Hz, 1H), 4.52-4.41 (m, 2H), 4.02(s, 3H), 1.26 (s, 9H), 1.05 (d, J=6.6 Hz, 3H). MS m/z 358.2 (M+H)⁺;Rt-1.00 min.

Intermediate 21:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(hydroxymethyl)pyrimidin-4-yl)oxazolidin-2-one

Sodium borohydride (60 mg, 1.59 mmol, 1.4 equiv) was added to asuspension of methyl6-((R)-4-((R)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-2-chloropyrimidine-4-carboxylate(400 mg, 1.12 mmol) in methanol (11.2 mL) at 0° C. The ice bath wasremoved and the reaction was stirred at room temperature for 1 hour. Thereaction was quenched with saturated aqueous ammonium chloride (100 mL)and extracted with ethyl acetate (3×50 mL). The combined extracts werewashed with saturated aqueous sodium chloride (30 mL), dried overNa₂SO₄, filtered and concentrated. Silica gel column chromatography(EtOAc/Heptane) provided(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(hydroxymethyl)pyrimidin-4-yl)oxazolidin-2-one(0.220 g, white solid) in 60% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.18 (s,1H), 4.77-4.72 (m, 3H), 4.66 (dd, J=9.4, 2.9 Hz, 1H), 4.48 (m, 1H), 4.41(m, 1H), 2.83 (m, 1H), 1.26 (s, 9H), 1.03 (d, J=6.6 Hz, 3H). MS m/z330.1 (M+H)⁺; Rt-0.86 min.

Intermediate 22:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(fluoromethyl)pyrimidin-4-yl)oxazolidin-2-one

N,N-Diethylaminosulfur trifluoride (0.13 mL, 0.98 mmol, 1.5 equiv) wasadded to a solution of(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(hydroxymethyl)pyrimidin-4-yl)oxazolidin-2-one(215 mg, 0.652 mmol) in DCM at −78° C. The reaction was stirred at −78°C. for 1 hour, then warmed to room temperature and stirred for anotherhour. Additional N,N-Diethylaminosulfur trifluoride (0.26 mL, 2.0 mmol,3 equiv) was added and the reaction stirred for another 1 hour. Thereaction was quenched with water (50 mL) and extracted with DCM (3×25mL). The combined extracts were washed with saturated aqueous sodiumchloride (30 mL), dried over Na₂SO₄, filtered and concentrated. Silicagel column chromatography (EtOAc/Heptane) provided(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(hydroxymethyl)pyrimidin-4-yl)oxazolidin-2-one(0.165 g, white solid) in 76% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s,1H), 5.40 (d, J=44 Hz, 1H), 4.75 (ddd, J=8.6, 4.1, 3.0 Hz, 1H), 4.67(dd, J=9.4, 2.9 Hz, 1H), 4.49 (m, 1H), 4.43 (m, 1H), 1.27 (s, 9H), 1.04(d, J=6.5 Hz, 3H). MS m/z 332.1 (M+H)⁺; Rt-1.02 min.

Intermediate 23:(S)-4,6-difluoro-N-(1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)pyrimidin-2-amine

(S)-1-(1-(4-Fluorophenyl)-1H-pyrazol-4-yl)ethanamine (175 mg, 0.724mmol) was added to a solution of 2,4,6-trifluoropyrimidine (146 mg, 1.09mmol, 1.5 equiv) and N-ethyl-N-isopropylpropan-2-amine (0.32 mL, 1.8mmol, 2.5 equiv) in 1,4-dioxane at room temperature. The mixture wasstirred at room temperature for 1 hour and then the reaction wasconcentrated in vacuo. Silica gel column chromatography (EtOAc/Heptane)provided(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-(hydroxymethyl)pyrimidin-4-yl)oxazolidin-2-one(0.085 g) in 37% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1H), 7.68 (s,1H), 7.62 (dd, J=8.9, 4.6 Hz, 1H), 7.18-7.11, (m, 2H), 5.80 (t, J=1.2Hz, 1H), 5.49 (m, 1H), 5.25 (m, 1H), 1.62 (d, J=6.8 Hz, 3H). MS m/z320.1 (M+H)⁺; Rt-0.95 min.

The Intermediates in Table 1a were prepared by a method similar to theone described for the preparation of Intermediate 23.

TABLE 1a

Intermediate 24

Intermediate 25

TABLE 1b Chemical name, NMR chemical shifts and LCMS signal for eachintermediate listed in Table 1a. Intermediate: Name ¹H NMR (400 MHz,CDCl₃) δ ppm LCMS 24: (S)-4,6-difluoro-N-(1-(1-(4-fluorophenyl)- 7.82(s, 1H), 7.68 (s, 1H), 7.62 MS m/z1H-pyrazol-4-yl)ethyl)pyrimidin-2-amine (dd, J = 8.9, 4.6 Hz, 1H),7.18-7.11, 320.1 (M + H)⁺; (m, 2H), 5.80 (t, J = 1.2 Hz, Rt-0.95 min1H), 5.49 (m, 1H), 5.25 (m, 1H), 1.62 (d, J = 6.8 Hz, 3H). 25:(S)-N-(1-(1-(4-chlorophenyl)-1H-pyrazol- MS m/z4-yl)ethyl)-4,6-difluoropyrimidin-2-amine 336.0 (M + H)⁺; Rt-1.04 min

Intermediate 26:(R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)oxazolidin-2-one

Imidazole (1.74 g, 25.6 mmol, 2.0 equiv) was added to a solution of(S)-4-(hydroxymethyl)oxazolidin-2-one (1.5 g, 12.8 mmol) andtert-butylchlorodiphenylsilane (3.95 mL, 15.4 mmol, 1.2 equiv) in DCM(43 mL) at room temperature. A white precipitate formed. The solutionwas stirred at room temperature for 16 hours and then diluted with water(50 mL). The layers were separated and the aqueous layer was extractedwith DCM (50 mL). The combined organic extracts were washed withsaturated aqueous sodium chloride (50 mL), dried over Na₂SO₄, filteredand concentrated. Silica gel column chromatography (EtOAc/Heptane 20 to65%) provided(R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)oxazolidin-2-one (3.55 g,sticky colorless oil) in 78% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (m,4H), 7.50-7.38 (m, 6H), 5.31 (m, 1H), 4.44 (t, J=8.7 Hz, 1H), 4.15 (m,1H), 4.00 (m, 1H), 3.65 (d, J=5.5 Hz, 2H), 1.07 (s, 9H). MS m/z 356.1(M+H)⁺; Rt-1.00 min.

Intermediate 27:(R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one

Sodium hydride (34 mg, 0.84 mmol, 1.5 equiv) was carefully added to asolution of (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)oxazolidin-2-one(200 mg, 0.563 mmol) in DMF (2.8 mL). The mixture was stirred at roomtemperature for 20 minutes and then 2,4-difluoropyrimidine (0.072 mL,0.84 mmol, 1.5 equiv) was added (bubbling). The yellow suspension wasstirred for 10 minutes and the reaction was then carefully quenched withsaturated aqueous ammonium chloride (5 mL). Water (20 mL) was added andthe mixture was extracted with ethyl acetate (2×25 mL). The combinedorganic extracts were washed with saturated aqueous sodium chloride (20mL), dried over Na₂SO₄, filtered and concentrated. Silica gel columnchromatography (EtOAc/Heptane 30%) provided(R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(0.185 g, sticky colorless oil) in 73% yield. ¹H NMR (400 MHz, CDCl₃) δ8.44 (dd, J=5.8, 2.2 Hz, 1H), 8.12 (dd, J=5.8, 3.4 Hz, 1H), 7.58 (m,2H), 7.48-7.32 (m, 6H), 7.23 (m, 2H), 4.80 (m, 1H), 4.65 (dd, J=8.6, 3.0Hz, 1H), 4.55 (m, 1H), 4.18 (dd, J=11.1, 3.5 Hz, 1H), 3.83 (dd, J=11.1,2.1 Hz, 1H), 1.04 (s, 9H). MS m/z 452.3 (M+H)⁺; Rt-1.15 min.

Intermediate 28:(S)-3-(2-fluoropyrimidin-4-yl)-4-(hydroxymethyl)oxazolidin-2-one

A solution of tetrabutylammonium fluoride (1.0 M in THF, 0.44 mL, 0.44mmol, 1.1 equiv) was added to a solution of(R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(180 mg, 0.40 mmol) in THF (4 mL) at room temperature. The solution wasstirred for 1 hour and then diluted with saturated aqueous sodiumchloride (30 mL). The mixture was extracted with ethyl acetate (2×30 mL)and the combined extracts were dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/Heptane) provided(S)-3-(2-fluoropyrimidin-4-yl)-4-(hydroxymethyl)oxazolidin-2-one (0.051g, white solid) in 60% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.51 (dd, J=5.8,2.1 Hz, 1H), 8.19 (dd, J=5.8, 3.8 Hz, 1H), 4.86 (dq, J=8.1, 4.0 Hz, 1H),4.55 (m, 2H), 4.09 (m, 1H), 3.96 (m, 1H), 2.18 (t, J=5.4 Hz, 1H). MS m/z214.0 (M+H)⁺; Rt-0.37 min.

Intermediate 29:(R)-4-(fluoromethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one

Perfluorobutanesulfonyl fluoride (0.18 mL, 0.98 mmol, 4 equiv) was addedto a solution of(S)-3-(2-fluoropyrimidin-4-yl)-4-(hydroxymethyl)oxazolidin-2-one (52 mg,0.24 mmol) in THF (1.2 mL) at room temperature. Triethylaminetrihydrofluoride (0.16 mL, 0.98 mmol, 4 equiv) and triethylamine (0.41mL, 3.0 mmol, 12 equiv) were then added and the solution was stirred at40° C. for 18 hours. The reaction was then cooled to room temperatureand diluted with water (25 mL). The mixture was extracted with ethylacetate (2×25 mL). The combined organic extracts were washed withsaturated aqueous sodium chloride (10 mL), dried over Na₂SO₄, filteredand concentrated. Silica gel column chromatography (EtOAc/Heptane)provided (R)-4-(fluoromethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(0.021 g, colorless oil) in 40% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.53(dd, J=5.7, 2.1 Hz, 1H), 8.18 (dd, J=5.7, 3.7 Hz, 1H), 5.08-4.93 (m,2H), 4.91-4.72 (m, 1H), 4.66-4.55 (m, 2H). MS m/z 215.9 (M+H)⁺; Rt-0.57min.

Intermediate 30:(R)-4-((R)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one

Step 1

To a round bottom flask containing a stir bar and(2S,3S)-2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)butanoic acid DCHA(10 g, 20.4 mmol) in THF (160 mL) under nitrogen was cooled to −30° C.in a dry ice/acetone bath. To this cold white suspension was addedisobutyl chloroformate (3.2 mL, 24.5 mmol) followed by the addition ofN-methylmorpholine (2.7 mL, 24.5 mmol). Mixture was stirred for 20 minat −30° C. A N-Methylmorpholine salt develops and was filtered frommixture. Mother liquor was cooled to −30° C. where upon sodiumborohydride (1.16 g, 30.6 mmol) was added followed by the addition ofwater (20 mL) immediately afterwards. Reaction mixture allowed to stirfor 15 min at −20° C. then gradually allowed to warm to roomtemperature. The reaction mixture was stirred for 30 min at roomtemperature. The reaction mixture was then diluted with water andextracted with EtOAc. Organic phases combined, washed with water, brine,dried (Na₂SO₄), filtered and concentrated to afford benzyl((2R,3S)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (5.27 g, 17.8mmol, 88% yield) as a colorless oil. LCMS m/z 296.1 (M+H)⁺, Rt 0.84 min.

Step 2

To a round bottom flask containing benzyl((2R,3S)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (5.27 g, 17.8mmol) was added MeOH (100 mL). Solution was degassed with nitrogen for15 min at which time palladium on carbon (0.95 g, 0.89 mmol) in MeOH (5mL) was added. A hydrogen atmosphere was then inserted. Resultingreaction mixture allowed to stir 40 min at room temperature atatmospheric pressure when water (2 mL) was added and once again ahydrogen atmosphere was inserted at atmospheric pressure and thesubsequent reaction mixture allowed to stir 18 hr at room temperature.The reaction mixture was filtered through a pad of celite andconcentrated to a brown oil. Oil redissolved in toluene and concentratedto afford (2R,3S)-2-amino-3-(tert-butoxy)butan-1-ol (2.5 g, 15.5 mmol,87% yield) as a brown oil. LCMS m/z 162.1 (M+H)⁺, Rt 0.41 min (Mass iononly, no UV peak).

Step 3

To a round bottom flask containing(2R,3S)-2-amino-3-(tert-butoxy)butan-1-ol (1.25 g, 7.75 mmol) and a stirbar was added acetonitrile (50 mL) followed by the addition of2,4-difluoropyrimidine (0.99 g, 8.53 mmol) and DIEA (4.1 mL, 23.3 mmol).The resulting reaction mixture allowed to stir 1 hr at room temperature.The volatiles were then removed. Residue was partitioned between EtOAcand water. Aqueous layer extracted with EtOAc. Organic phases combined,washed with water, brine, dried (Na₂SO₄), filtered and concentrated to aviscous yellow oil of(2R,3S)-3-(tert-butoxy)-2-((2-fluoropyrimidin-4-yl)amino)butan-1-ol (1.5g, 5.83 mmol, 75% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.14 (s, 9H) 1.31(d, J=6.26 Hz, 3H) 3.64 (d, J=12.91 Hz, 2H) 3.86 (br. s., 1H) 4.26 (d,J=10.17 Hz, 1H) 6.09 (br. s., 1H) 6.25 (br. s., 1H) 7.99 (br. s., 1H).LCMS m/z 258.2 (M+H)⁺, Rt 0.62 min

Step 4

To a round bottom flask containing(2R,3S)-3-(tert-butoxy)-2-((2-fluoropyrimidin-4-yl)amino)butan-1-ol (1.5g, 5.83 mmol) and a stir bar under nitrogen was added DCM (58 mL). Theresulting reaction mixture cooled to −70° C. in a dry ice/acetone bath.To this cold solution was added triphosgene (0.95 g, 3.21 mmol) followedby the addition of 2,6-dimethylpyridine (2.7 ml, 23.3 mmol). Theresulting reaction mixture allowed to warm to room temperature andstirred for 1 hr.

The reaction mixture was then diluted with DCM and water and allowed tostir 1 hr at room temperature. The phases were then partioned andaqueous phase extracted with DCM. Organic phases combined, washed withwater, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel.Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(502 mg, 1.77 mmol, 30% yield) as a white crystalline. LCMS m/z 284.1(M+H)⁺, Rt 0.89 min.

Step 5

To a round bottom flask containing(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(502 mg, 1.77 mmol) was added DCM (4 mL) and TFA (4 mL). Resultingreaction mixture stirred for 1 hr at room temperature. The volatileswere then removed and the residue neutralized with a saturated solutionof NaHCO₃. The aqueous mixture was extracted with EtOAc. Organic phasescombined, washed with water, brine, dried (Na₂SO₄), filtered andconcentrated to a colorless residue of(R)-3-(2-fluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one(382 mg, 1.68 mmol, 95% yield). LCMS m/z 228.1 (M+H)⁺, Rt 0.44 min.

Step 6

To a round bottom flask containing a solution of(R)-3-(2-fluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one(348 mg, 1.53 mmol) in THF (5.1 mL) was added perfluorobutanesulfonylfluoride (0.83 mL, 4.60 mmol) followed by the addition of triethylaminetrihydrofluoride (0.75 mL, 4.60 mmol) and triethylamine (1.9 mL, 13.8mmol). The resulting reaction mixture allowed to stir at roomtemperature for 6 hr. The reaction mixture was diluted with water andthe aqueous mixture was extracted with EtOAc. Organic phases combined,washed with water, brine, dried (Na₂SO₄), filtered and concentrated ontosilica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 60%)provided a viscous oil of(R)-4-((R)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(125 mg, 0.44 mmol, 28% yield) which crystallizes upon standing. ¹H NMR(400 MHz, CDCl₃) δ 1.34 (dd, J=24.26, 6.65 Hz, 3H) 4.45-4.55 (m, 1H)4.61-4.68 (m, 1H) 5.11 (dt, J=7.63, 4.01 Hz, 1H) 5.30-5.52 (m, 1H)8.13-8.17 (m, 1H) 8.52 (d, J=5.87 Hz, 1H). LCMS m/z 230.0 (M+H)⁺, Rt0.66 min.

Intermediate 31:(R)-3-(2,5-difluoropyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one

Step 1

To a round bottom flask containing(2R,3S)-2-amino-3-(tert-butoxy)butan-1-ol (1.25 g, 7.75 mmol) and a stirbar was added acetonitrile (50 mL) followed by the addition of2,4,5-trifluoropyrimidine (1.04 g, 7.75 mmol) and DIEA (4.1 mL, 23.3mmol). The resulting reaction mixture allowed to stir 1 hr at roomtemperature. The volatiles were then removed. Reaction mixture was thenpartitioned between EtOAc and water. Aqueous layer extracted with EtOAc.Organic phases combined, washed with water, brine, dried (Na₂SO₄),filtered and concentrated to a viscous yellow oil of(2R,3S)-3-(tert-butoxy)-2-((2,5-difluoropyrimidin-4-yl)amino)butan-1-ol(1.56 g, 5.67 mmol, 73% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.15 (s, 9H)1.32 (d, J=6.26 Hz, 3H) 3.45 (br. s., 1H) 3.67 (d, J=11.35 Hz, 1H)3.85-3.92 (m, 1H) 4.27 (d, J=11.74 Hz, 1H) 6.29 (d, J=5.48 Hz, 1H) 7.87(d, J=2.35 Hz, 1H). LCMS m/z 276.4 (M+H)⁺, Rt 0.71 min.

Step 2

To a round bottom flask containing(2R,3S)-3-(tert-butoxy)-2-((2,5-difluoropyrimidin-4-yl)amino)butan-1-ol(1.56 g, 5.67 mmol) and a stir bar under nitrogen was added DCM (57 mL).The resulting reaction mixture cooled to −70° C. in a dry ice/acetonebath. To this cold solution was added triphosgene (0.93 g, 3.12 mmol)followed by the addition of 2,6-dimethylpyridine (2.64 ml, 22.7 mmol).The resulting reaction mixture allowed to warm to room temperature andstirred 90 hr at room temperature. The reaction mixture was then dilutedwith DCM and water and allowed to stir 1 hr at room temperature. Thephases were then partioned and aqueous phase extracted with DCM. Organicphases combined, washed with water, brine, dried (Na₂SO₄), filtered andconcentrated onto silica gel. Silica gel column chromatography(EtOAc/Heptane 0 to 100%) provided(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one(0.59 g, 1.96 mmol, 35% yield) as a white crystalline. ¹H NMR (400 MHz,CDCl₃) δ 1.03 (s, 9H) 1.16 (d, J=6.65 Hz, 3H) 4.15 (qd, J=6.39, 1.96 Hz,1H) 4.43-4.52 (m, 1H) 4.59-4.72 (m, 2H) 8.43 (d, J=1.57 Hz, 1H). LCMSm/z 246.0 (-t-butyl fragment) (M+H)⁺, Rt 0.88 min.

Step 3

To a round bottom flask containing(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one(590 mg, 1.96 mmol) was added DCM (4 mL) and TFA (4 mL). Resultingreaction mixture stirred for 1 hr at room temperature. The volatileswere then removed. Residue neutralized with a saturated solution ofNaHCO₃ and aqueous mixture extracted with EtOAc. Organic phasescombined, washed with water, brine, dried (Na₂SO₄), filtered andconcentrated to a colorless residue of(R)-3-(2,5-difluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one(470 mg, 1.917 mmol, 98% yield). LCMS m/z 246.0 (M+H)⁺, Rt 0.41 min.

Step 4

To a round bottom flask containing a solution of(R)-3-(2,5-difluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one(0.47 g, 1.917 mmol) in THF (6.4 mL) was added perfluorobutanesulfonylfluoride (1.03 mL, 5.75 mmol) followed by the addition of triethylaminetrihydrofluoride (0.94 mL, 5.75 mmol) and triethylamine (2.40 mL, 17.3mmol) resulting reaction mixture allowed to stir at room temperature for6 hr. The reaction mixture was diluted with water and the aqueousmixture was extracted with EtOAc. Organic phases combined, washed withwater, brine, dried (Na₂SO₄), filtered and concentrated onto silica gel.Silica gel column chromatography (EtOAc/Heptane 0 to 60%) provided awhite crystalline of(R)-3-(2,5-difluoropyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one(150 mg, 0.61 mmol, 32% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.37 (dd,J=24.26, 6.26 Hz, 3H) 4.48 (dd, J=9.39, 4.70 Hz, 1H) 4.63 (t, J=8.80 Hz,1H) 4.90-5.02 (m, 1H) 5.02-5.25 (m, 1H) 8.50 (s, 1H). LCMS m/z 248.0(M+H)⁺, Rt 0.59 min.

Intermediate 32

Step 1

To a round bottom flask containing(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(2.1 g, 7.41 mmol) was added DCM (18.5 mL) and TFA (18.5 mL). Theresulting reaction mixture stirred for 1 hr at room temperature. Thevolatiles were then removed and the residue neutralized with a saturatedsolution of NaHCO₃. The aqueous mixture was then extracted with EtOAc.The organic phases were combined, washed with water, brine, dried(Na₂SO₄), filtered and concentrated to a colorless residue of(R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one(1.52 g, 6.69 mmol, 90% yield) which crystallizes upon standing. LCMSm/z 228.0 (M+H)⁺, Rt 0.44 min.

Step 2

To a round bottom flask containing a solution of(R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one(1.52 g, 6.69 mmol) in THF (22 mL) was added perfluorobutanesulfonylfluoride (3.6 mL, 20.1 mmol) followed by the addition of triethylaminetrihydrofluoride (3.3 mL, 20.1 mmol) and triethylamine (8.4 mL, 60.2mmol). The resulting reaction mixture allowed to stir at roomtemperature for 2 hr. The reaction mixture was then diluted with waterand the aqueous mixture was extracted with EtOAc. The organic phasescombined, washed with water, brine, dried (Na₂SO₄), filtered andconcentrated onto silica gel. Silica gel column chromatography(EtOAc/Heptane 0 to 60%) provided a white crystalline of(R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(207 mg, 0.90 mmol, 14% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.44 (dd,J=23.48, 6.26 Hz, 3H) 4.47-4.57 (m, 1H) 4.66 (dd, J=8.80, 3.33 Hz, 1H)4.71-4.86 (m, 1H) 5.22-5.45 (m, 1H) 8.21 (dd, J=5.48, 3.91 Hz, 1H) 8.52(dd, J=5.48, 1.96 Hz, 1H). LCMS m/z 230.1 (M+H)⁺, Rt 0.63 min.

Alternative Method for Making Intermediate 32:

To a cooled (0° C.) solution of 2,4-difluoropyrimidine (160 mg, 1.375mmol) and (R)-4-((S)-1-fluoroethyl)oxazolidin-2-one (183 mg, 1.375 mmol)in DMF (Volume: 4.6 mL) was added NaH (60% in mineral oil, 66.0 mg,1.650 mmol). The resulting mixture was stirred at 0° C. for 30 min andat room temperature for 2 hr. Desired product was observed from LC-MS.The mixture was quenched with brine (1 ml). Diluted w/ EtOAc (20 ml) andwater (10 ml), and separated layers. The organic was extracted with anadditional 20 mL EtOAc. The combined organics were washed with brine,dried, and concentrated. Crude was purified through flash columnchromatography (10-100% EtOAc/Heptane) to give(R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one,210 mg white solid. 1H NMR (400 MHz, CDCl3) δ 8.51 (dd, J=5.8, 2.1 Hz,1H), 8.20 (dd, J=5.7, 3.7 Hz, 1H), 5.33 (dqd, J=49.5, 6.6, 1.3 Hz, 1H),4.77 (dddd, J=26.5, 9.1, 3.4, 1.4 Hz, 1H), 4.65 (dd, J=9.0, 3.4 Hz, 1H),4.50 (td, J=9.0, 1.3 Hz, 1H), 1.43 (dd, J=23.1, 6.6 Hz, 3H). MS m/z230.1 (M+H).

Intermediate 33: 4-(2-fluoropropan-2-yl)oxazolidin-2-one

Step 1: Preparation of 2-amino-3-fluoro-3-methylbutan-1-ol

To the solution of LiBH₄ (2M in THF, 7.40 mL, 14.8 mmol) andtrimethylchlorosilane (3.78 mL, 29.6 mmol) in THF (7 mL) was added3-fluoro-D,L-valine (1 g, 7.40 mmol). The resulting mixture was stirredat room temperature for 24 hr. The reaction mixture was quenched withmethanol and then concentrated under reduced pressure to give an oilyproduct. The oily product was diluted with DCM and 10% aqueous sodiumbicarbonate solution and then stirred at room temperature for ˜16 hr.The separated organic layer was washed with saturated aqueous sodiumbicarbonate solution and brine, dried over sodium sulfate, filtered offand concentrated under reduced pressure providing2-amino-3-fluoro-3-methylbutan-1-ol (350 mg) as a solid, which was usedwithout further purification. MS m/z 121.9 (M+H)⁺; Rt-0.16 min.

Step 2: Preparation of 4-(2-fluoropropan-2-yl)oxazolidin-2-one

To a solution of N,N′-carbonyldiimidazole (530 mg, 3.27 mmol in THF (5mL) was added slowly a solution of 2-amino-3-fluoro-3-methylbutan-1-ol(360 mg, 2.97 mmol) in THF (10 mL). The reaction mixture was stirred atroom temperature for 18 hr, was diluted with DCM and stirred foradditional 30 min. The separated organic layer was washed with water andbrine, dried over sodium sulfate, filtered off and concentrated underreduced pressure. The residue was purified by column chromatography[SiO₂, 12 g, EtOAc/heptane=0/100 to 80/20] to provide4-(2-fluoropropan-2-yl)oxazolidin-2-one (150 mg) as a brown solid. MSm/z 148.0 (M+H)⁺; Rt-0.32 min. ¹H NMR (400 Mhz, CDCl₃) δ ppm 6.30 (br.s., 1H), 4.39-4.54 (m, 1H), 4.26 (dd, J=8.9, 5.1 Hz, 1H), 3.84-3.99 (m,1H), 1.29-1.45 (m, 6H).

Intermediate 34:3-(2-chloropyrimidin-4-yl)-4-(2-fluoropropan-2-yl)oxazolidin-2-one

To the solution of 2,4-dichloropyrimidine (150 mg, 1.006 mmol) and4-(2-fluoropropan-2-yl)oxazolidin-2-one (148 mg, 1.01 mmol) in DMF (4.5mL), sodium hydride (60% wt. 89 mg, 2.21 mmol) was added to give a paleyellow mixture. The mixture was stirred at room temperature for 2 hr,diluted with EtOAc and stirred for additional 30 min. The separatedorganic layer was washed with saturated aqueous sodium bicarbonatesolution, water and brine. The organic phase was dried over sodiumsulfate, filtered off and concentrated under reduced pressure. Theresidue was purified by column chromatography [SiO₂, 12 g,EtOAc/heptane=0/100 to 80/20] providing3-(2-chloropyrimidin-4-yl)-4-(2-fluoropropan-2-yl)oxazolidin-2-one (150mg) as a brown solid. MS m/z 260.1 (M+H)⁺; Rt-0.72 min. ¹H NMR (400 Mhz,CDCl₃) δ ppm 8.51 (d, J=5.9 Hz, 1H), 8.17 (d, J=5.9 Hz, 1H), 5.14 (dd,J=17.4, 8.0 Hz, 1H), 4.66 (d, J=9.4 Hz, 1H), 4.43-4.52 (m, 1H),1.42-1.52 (m, 3H), 1.30-1.40 (m, 3H).

Intermediate 35: (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one

Step 1: Preparation of (S)-benzyl3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate

-   Reference: V. L. Truong, et al.; Synlett 2005, 8, 1279-1280.

To a solution of Boc-Asp(OBnzl)-OH (20 g, 61.9 mmol) in DME (60 mL) at−40° C. (dry ice/acetonitrile bath) was added N-methylmorpholine (7.07mL, 64.3 mmol) over 5 min followed by isobutyl chloroformate (8.53 ml,64.9 mmol) dropwise over 15 min, keeping the temperature below −10° C.The mixture was stirred for 30 min (−30° C. to −40° C.). The solids werequickly filtered off and rinsed with DME (60 mL). The clear filtrate wascooled to −35° C. and a solution of NaBH₄ (2.93 g, 78 mmol) in 30 mLwater was added dropwise maintaining a temperature between −30° C. and−15° C. [Caution: gas deveopment]. Water (332 mL) was added dropwiseover 30 min to the white suspension maintaining a temperature below −15°C. The thick white slurry was filtered, rinsed with water (300 mL). Thefiltered solid was dissolved in DCM (250 mL). The solution was driedover sodium sulfate, filtered off and concentrated under reducedpressure to provide (S)-benzyl3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate (16.35 g) as a whitesolid. MS m/z 254.2 (M-tert-butyl)⁺; Rt-0.78 min. ¹H NMR (400 Mhz,D₃C(CO)CD₃) δ ppm 7.45-7.28 (m, 4H), 5.92-5.80 (m, 1H), 5.11 (s, 2H),4.07-3.91 (m, 1H), 3.67-3.48 (m, 2H), 2.82-2.77 (m, 1H), 2.74-2.68 (m,1H), 2.61-2.52 (m, 1H), 1.39 (s, 9H).

Step 2: Preparation of (S)-benzyl 2-(2-oxooxazolidin-4-yl)acetate

-   Reference: V. L. Truong, et al.; Synlett 2005, 8, 1279-1280.

To a solution of (S)-benzyl3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate (16.3 g, 52.7 mmol)and pyridine (10.65 ml, 132 mmol) in DCE (157 mL) at 0° C. was addedp-toluenesulfonic anhydride (17.10 g, 52.4 mmol) in two portions over 5min. The mixture was stirred for a few minutes, then allowed to warm toroom temperature and stirred for 1 hr. The mixture was heated for 6 hrat 92° C. and then allowed to cool to room temperature. The mixture wasdiluted with DCM (80 mL), washed with 1N aqueous HCl solution (2×200mL), brine (200 mL), and saturated aqueous sodium bicarbonate solution(100 mL). The organic layer was dried over sodium sulfate, filtered offand concentrated under reduced pressure. The residue was purified bycolumn chromatography [SiO₂, 220 g, EtOAc/heptane=5/95 to 75/25] toprovide (S)-benzyl 2-(2-oxooxazolidin-4-yl)acetate (10.0 g) as a whitesolid. MS m/z 236.2 (M+H)⁺; Rt-0.59 min.

Step 3: Preparation of (R)-benzyl 2-((S)-2-oxooxazolidin-4-yl)propanoate

To a solution of sodium bis(trimethylsilyl)amide (1M in THF; 68.0 mL)under argon atmosphere was added THF (40.4 mL). The mixture was cooledto −78° C. and a solution of (S)-benzyl 2-(2-oxooxazolidin-4-yl)acetate(7.80 g, 33.2 mmol) in THF (85 mL) was added slowly over ˜15 min. Themixture was stirred for 1 hr at −78° C. and a solution of iodomethane(4.25 mL, 68.0 mmol) in THF (40.4 mL) was added slowly over ˜10 min. Thereaction mixture was stirred for 1 hr at −78° C. and ˜1 hr at −40° C.The mixture was quenched with saturated aqueous ammonium chloridesolution (˜100 mL) and allowed to warm to room temperature. The mixturewas extracted with DCM (3×). The combined organic layers were dried oversodium sulfate, filtered off and concentrated under reduced pressure.The residue was purified by column chromatography [SiO₂, 220 g,EtOAc/heptane] to provide (R)-benzyl2-((S)-2-oxooxazolidin-4-yl)propanoate (7.47 g) as a colorless oil. MSm/z 250.1 (M+H)⁺; Rt-0.65 min. ¹H NMR (400 Mhz, DMSO-d6) δ ppm 7.85 (s,1H), 7.44-7.28 (m, 5H), 5.10 (s, 2H), 4.36 (t, J=1.0 Hz, 1H), 4.11 (dd,J=5.4, 8.9 Hz, 1H), 4.06-3.98 (m, 1H), 2.69 (quin, J=6.9 Hz, 1H), 1.08(d, J=7.1 Hz, 3H).

Step 4: Preparation of (R)-2-((S)-2-oxooxazolidin-4-yl)propanoic Acid

To a solution of (R)-benzyl 2-((S)-2-oxooxazolidin-4-yl)propanoate (1.99g, 7.98 mmol) in THF (18.7 mL) was added Pd/C (10% wt., Degussa; 0.425g). The mixture was stirred under hydrogen atmosphere (balloon) at roomtemperature for 4 hr. The mixture was filtered through a plug of celiteand rinsed several times with THF. The filtrate was concentrated underreduced pressure providing (R)-2-((S)-2-oxooxazolidin-4-yl)propanoicacid (1.17 g) as a white solid, which was directly used without furtherpurification. MS m/z 160.0 (M+H)⁺; Rt-0.26 min. ¹H NMR (400 Mhz, CD₃OD)δ ppm 4.53-4.47 (m, 1H), 4.26 (dd, J=5.7, 9.1 Hz, 1H), 4.13 (td, J=6.0,8.8 Hz, 1H), 2.69-2.61 (m, 1H), 1.18 (d, J=7.2 Hz, 3H).

Step 5: Preparation of(R)—N-methoxy-N-methyl-2-((S)-2-oxooxazolidin-4-yl)propanamide

To a mixture of (R)-2-((S)-2-oxooxazolidin-4-yl)propanoic acid (1.1 g,6.91 mmol) in DCM (20 mL) was added1-chloro-N,N,2-trimethylprop-1-en-1-amine (1.385 g, 10.37 mmol) at 0° C.The ice bath was removed and the mixture was stirred for 30 min atambient temperature. A mixture of N,O-dimethylhydroxylamine (1.011 g,10.37 mmol) and pyridine (1.677 mL, 20.74 mmol) in DCM (20 mL) was addedand stirring was continued for ˜1 hr. The mixture was diluted with water(˜2 mL) and saturated sodium bicarbonate solution (˜2 mL) and stirredfor ˜15 min. The mixture was diluted with dichloromethane (˜30 mL). Theseparated aqueous layer was extracted with DCM (1×), the organic layerswere combined, dried over sodium sulfate, filtered and concentratedunder reduced pressure providing crude(R)—N-methoxy-N-methyl-2-((S)-2-oxooxazolidin-4-yl)propanamide (2.73 g)as an orange oil which was directly used without further purification.MS m/z 203.1 (M+H)⁺; Rt-0.36 min.

Step 6: Preparation of(R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)-N-methoxy-N-methylpropanamide

To a mixture of crude(R)—N-methoxy-N-methyl-2-((S)-2-oxooxazolidin-4-yl)propanamide (1.3 g,6.43 mmol) and (bromomethyl)benzene (1.30 mL, 11.4 mmol) in THF (25 mL)was added slowly sodium hydride (60% wt.; 0.643 g) at 0° C. [Caution:gas development!]. The ice bath was removed and the mixture was stirredfor ˜2 hr. The mixture were diluted carefully with water and ethylacetate. The reaction was repeated on the same scale and the mixtureswere combined. The aqueous layer was separated and extracted with ethylacetate (1×). The combined organic layers were dried over sodiumsulfate, filtered off and concentrated under reduced pressure. Theresidue was purified by column chromatography [SiO₂, 80 g,EtOAc/heptane=5/95 to 75/25] to provide(R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)-N-methoxy-N-methylpropanamide(1.83 g) as a slightly yellow oil, which contained alsoN-methoxy-N-methylisobutyramide. MS m/z 293.7 (M+H)⁺; Rt-0.64 min.

Step 7: Preparation of (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)propanal

To a solution of(R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)-N-methoxy-N-methylpropanamidefrom Step 6 (1.5 g, 5.13 mmol) in THF (30 mL) was added dropwise DIBAL-H(1M solution in hexane; 11.29 mL) at −78° C. The mixture was stirred for90 min at −78° C., diluted slowly with Rochelle's salt solution (1Msolution in water; ˜20 mL) and stirred vigrously for ˜15 min. Theaqueous layer was separated and extracted with ethyl acetate (3×). Thecombined organic extracts were washed with saturated sodium bicarbonatesolution and brine, filtered through a mixture of celite/silica gel. Thefiltrate was concentrated under reduced pressure providing crude(R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)propanal (1.26 g) as acolorless oil, which was directly used without further purification. MSm/z 234.2 (M+H)⁺; Rt-0.60 min.

Step 8: Preparation of(S)-3-benzyl-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one

To a solution of (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)propanal (1.26g, 5.40 mmol) in DCM (13 mL) was added slowly DAST (2.85 mL, 21.6 mmol)at 0° C. The mixture was allowed to warm to room temperature and stirredovernight. The mixture was carefully diluted with ice-water. Theseparated aqueous layer was extracted with DCM (3×). The combinedorganic layers were dried over sodium sulfate, filtered off andconcentrated under reduced pressure. The residue was purified by columnchromatography [SiO₂; 80 g, ethylacetate/heptane] providing(S)-3-benzyl-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (627 mg) asa slightly yellowish oil. MS m/z 255.7/257.3 (M+H)⁺; Rt-0.80 min. ¹H NMR(400 Mhz, CD₃OD) δ ppm 7.31-7.43 (m, 5H), 5.86 (dt, J=1.0 Hz, 1H), 4.70(d, J=15.3 Hz, 1H), 4.32 (d, J=7.4 Hz, 2H), 4.23 (d, J=15.7 Hz, 1H),4.06 (td, J=7.4, 2.7 Hz, 1H), 2.40-2.59 (m, 1H), 0.98 (d, J=7.0 Hz, 3H).

Step 9: Preparation of(S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one

To liquid ammonia at −50° C. under argon was slowly added a solution of(S)-3-benzyl-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (627 mg)(200 mg, 0.784 mmol) in diethylether (10 mL). Lithium (pellets; 54.4 mg,7.84 mmol) were added in three portions. The reaction mixture becamegreen then dark greenish blue over ˜10 min. The mixture was stirred foradditional 15 min and then quenched slowly by the addition of saturatedaqueous ammonium chloride solution (3 mL). The mixture was allowed towarm slowly to room temperature. The residue was diluted withdiethylether (20 mL) and water (10 mL). The separated aqueous layer wasextract with ether (2×25 mL) and DCM (3×20 mL). The DCM and ether layerswere separately concentrated under reduced pressure. The residues weredissolved in DCM and combined. The organic layer was dried overmagnesium sulfate, filtered off and concentrated under reduced pressureproviding crude (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (114mg) as a colorless solid, which was directly used without furtherpurification. MS m/z 166.1 (M+H)⁺; Rt-0.37 min.

Intermediate 36:(S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one

To a solution of (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one(223 mg, 1.35 mmol) and 2,4-difluoropyrimidine (157 mg, 1.35 mmol) inDMF (4.09 mL) was added sodium hydride (60% wt.; 70.2 mg) in threeportions at <0° C. (sodium chloride/ice). After the first portion ofsodium hydride the mixture was stirred for ˜5 min. The remaining twoportions of sodium hydride were added over ˜5 min and stirring wascontinued for 30 min. The mixture was diluted with ethylacetate (10 mL),stirred for 5 min and further slowly diluted with brine/water (1/1; 10mL). The mixture was allowed to warm to 5° C. and poured into a mixtureof brine/water (1/1; 20 mL) and ethylacetate (20 mL). The aqueous layerwas separated and extracted with ethylacetate (25 mL). The combinedorganic layers were washed with brine (40 mL), dried over sodiumsulfate, filtered off and concentrated under reduced pressure. Theresidue was purified by column chromatography [SiO₂, 12 g,EtOAc/heptane] to provide(S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(207 mg) as a white solid.

MS m/z 262.1 (M+H)⁺; Rt-0.72 min. ¹H NMR (400 Mhz, CD₃OD) δ ppm 8.55(dd, J=2.3, 5.8 Hz, 1H), 8.17 (dd, J=3.8, 5.8 Hz, 1H), 6.02 (q, J=1.0Hz, 1H), 5.17 (td, J=3.1, 8.3 Hz, 1H), 4.62-4.52 (m, 2H), 3.11-2.88 (m,1H), 1.05 (dd, J=0.7, 7.2 Hz, 3H).

Intermediate 37:(S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one

To a solution of (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one(114 mg, 069 mmol) and 2,4-dichloro-5-fluoropyrimidine (115 mg, 0.690mmol) in DMF (2.26 mL) was added sodium hydride (60% wt.; 35.9 mg) inthree portions at <0° C. (sodium chloride/ice). After the first portionof sodium hydride the mixture was stirred for ˜5 min. The remaining twoportions of sodium hydride were added over ˜5 min and stirring wascontinued for 30 min. The mixture was diluted with ethylacetate (10 mL),stirred for 5 min and further slowly diluted with brine/water (1/1; 10mL). The mixture was allowed to warm to 5° C. and poured into a mixtureof brine/water (1/1; 10 mL) and ethylacetate (10 mL). The aqueous layerwas separated and extracted with ethylacetate (25 mL). The combinedorganic layers were washed with brine (30 mL), dried over sodiumsulfate, filtered off and concentrated under reduced pressure. Theresidue was purified by column chromatography [SiO₂, 12 g,EtOAc/heptane] to provide(S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one(134 mg) as a white solid. MS m/z 296.1 (M+H)⁺; Rt-0.75 min. ¹H NMR (400Mhz, CD₃OD) δ ppm 8.69 (d, J=2.6 Hz, 1H), 5.99 (q, J=1.0 Hz, 1H), 5.17(ddd, J=3.5, 7.4, 8.6 Hz, 1H), 4.69-4.50 (m, 2H), 2.88-2.70 (m, 1H),1.04 (d, J=7.1 Hz, 3H).

Intermediate 38: 2-(1-azidoethyl)-5-(4-chlorophenyl)-4-methyloxazole

Sodium azide (635 mg, 9.760 mmol) and a catalytic amount of1,4,7,10,13,16-hexaoxacyclooctadecane was added to a solution of2-(1-chloroethyl)-5-(4-chlorophenyl)-4-methyloxazole (250 mg, 0.976mmol) in acetonitrile (10 ml) and refluxed at 80° C. for 3 hours. Thereaction was concentrated in vacuo. Flash column chromatography (silica,40 g) eluting with 0-5% EtOAc/DCM provided the title compound (254 mg,clear oil). HRMS(C) tR=1.52 min; MS m/z 262.0621

Intermediate 39: 1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethanamine

SiliaBond®Diphenylphosphine (1500 mg, 1.19 mmol/g) was added to asolution of 2-(1-azidoethyl)-5-(4-chlorophenyl)-4-methyloxazole (366 mg,1.393 mmol) in anhydrous methanol (15 ml) and shaken for 3 hours. Thereaction was filtered and concentrated in vacuo. Flash columnchromatography (silica, 40 g) eluting with 2-10% MeOH/DCM afforded 160mg (white solid). HRMS(B) tR=1.73 min; MS m/z 236.0716

Intermediate 40:(2S)—N-(2-(4-chlorophenyl)-2-hydroxyethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide

A solution of 2-amino-1-(4-chlorophenyl)ethanol (1000 mg, 5.83 mmol) and(S)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (1280 mg, 5.83 mmol) inTHF (20 ml) was added N,N′-methanediylidenedicyclohexanamine (1.1 eq,1322 mg, 6.41 mmol) and allowed to stir at ambient temperature for 12hours. Concentrate in vacuo, dilute w/ EtOAc, filter washing w/ EtOAc,wash w/ water, brine, concentrate in vacuo. Used crude directly in thenext step. 2 g of white solid. HRMS(B) tR=1.04 min; MS m/z 373.1

Intermediate 41:(S)—N-(2-(4-chlorophenyl)-2-oxoethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide

1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (3.091 g, 7.29mmol) was added to a solution of(2S)—N-(2-(4-chlorophenyl)-2-hydroxyethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide(2.173 g, 5.83 mmol) in dichloromethane (20 ml) and allowed to stir for2 hours. Dilute w/ dichloromethane (50 ml), wash w/ a sol'n of sat.sodium bicarbonate and 10% Na₂S₂O₃ solution, dry, concentrate in vacuo.2.162 g (Used directly in the next step without further purification.HRMS(B) tR=1.24 min; MS m/z 371.2

Intermediate 42:(S)-2-(1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)isoindoline-1,3-dione

Phosphoryl trichloride (1.m7 ml, 10.8 mmol) was added to a solution of(S)—N-(2-(4-chlorophenyl)-2-oxoethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide(2.162 g, 5.83 mmol) in toluene and heated at 110° C. for 15 hours.Dilute with dichloromethane (50 ml), wash with saturated sodiumbicarbonate solution, water, brine, dried and concentrated in vacuo.Flash column chromatography (silica, 80 g) eluting with 0-50% EtOAc/DCMafforded the pure product 430 mg (yellow foam). HRMS(B) tR=1.42 min; MSm/z 353.1

Intermediate 43:(S)-2-(1-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)isoindoline-1,3-dione

To a stirred solution of (Z)-3-chloro-N′-hydroxybenzimidamide (500 mg,2.93 mmol) and (S)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (642 mg,2.93 mmol) was added N,N′-methanediylidenedicyclohexanamine (1.1 eq, 665mg, 3.22 mmol) and allowed to reflux at 100° C. for 12 hours.Concentrate in vacuo, dilute w/ EtOAc, filter washing w/ EtOAc, wash w/water, brine, concentrate in vacuo. Flash column chromatography (silica,40 g) eluting w/ 0-10% EtOAc/DCM afforded 300 mg. HRMS m/z 353.0567

Intermediate 44: (S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethanamine

Hydrazine (0.55 ml, 6.09 mmol) was added to a solution of(S)-2-(1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)isoindoline-1,3-dione (430mg, 1.219 mmol) in ethanol (15 ml) and heated at 80° C. for 13 hours.The reaction was concentrated in vacuo. Flash column chromatography(silica, 40 g) eluting with 2-10% MeOH/DCM afforded the desired product(200 mg, yellow oil). ¹H NMR (400 MHz, CDCl₃) δ 7.67-7.51 (m, 9H),7.47-7.35 (m, 8H), 7.31-7.21 (m, 1H), 4.25 (q, J=6.8 Hz, 4H), 1.97-1.66(m, 15H), 1.63-1.48 (m, 2H). HRMS(B) tR=1.49 min; MS m/z 222.0560

Intermediate 45:(Z)-3-chloro-N′-hydroxy-4-(trifluoromethoxy)benzimidamide

To a solution of 3-chloro-4-(trifluoromethoxy)benzonitrile (1.0 g, 4.51mmol) and hydroxylamine hydrochloride (1.5 eq, 0.47 g, 6.77 mmol) inethanol (10 ml) was added N-ethyl-N-isopropylpropan-2-amine (1.6 eq,1.26 ml, 7.22 mmol) and refluxed at 80° C. for 12 hours under N₂. Allowto cool to rt. Dilute with EtOAc (25 ml), wash with water (25 ml), brine(25 ml), dry, concentrate in vacuo afforded(Z)-3-chloro-N′-hydroxy-4-(trifluoromethoxy)benzimidamide (0.71 g,62.1%, white solid). Used crude in the next step. HRMS(B) m/z 254.0070

The intermediates in Table 2a were prepared using a method similar tothat described for the preparation of Intermediate 45

TABLE 2a

Intermediate 46

Intermediate 47

Intermediate 48

Intermediate 49

Intermediate 50

Intermediate 51

Intermediate 52

Intermediate 53

Intermediate 54

Intermediate 55

Intermediate 56

Intermediate 57

Intermediate 58

Intermediate 59

Intermediate 60

Intermediate 61

Intermediate 62

Intermediate 63

Intermediate 64

TABLE 2b Chemical name and analytical data for each intermediate listedin Table 2a. Intermediate: Name Analytical data 46:(Z)-4-bromo-N′-hydroxy-3- HRMS(B) tR = 1.24 min; MS m/zmethoxybenzimidamide 243.9847. 47: (Z)-4-chloro-N′-hydroxy-3- HRMS(B) tR= 1.35 min; MS m/z methylbenzimidamide 184.0403 48:(Z)-N′-hydroxy-1,2-dimethyl- HRMS(B) tR = 1.13 min; MS m/z1H-indole-4-carboximidamide 203.1059 49: (Z)-N′-hydroxy-2- HRMS(B) tR =1.20 min; MS m/z (trifluoromethoxy)benzimidamide 220.0460 50:(Z)-2,2-difluoro-N′-hydroxy- HRMS(B) tR = 1.33 min; MS m/zbenzo[d][1,3]dioxole- 216.0347 5-carboximidamide 51:(Z)-N′-hydroxy-3-(2,2,2- HRMS(B) tR = 1.46 min; MS m/ztrifluoroethoxy)benzimidamide 234.061 52: (Z)-4-chloro-N′-hydroxy-HRMS(B) tR = 1.44 min; MS m/z 3-(trifluoromethoxy) benzimidamide254.0070 53: (Z)-N′-hydroxyisoquinoline- Anal. RP-HPLC tR = 0.93 min8-carboximidamide (Gradient: 1 to 30% B in 3.2 min to 98% in 1.95 min. -flow 1 mL/ min. Eluent A: Water + 3.75 mM NH4Ac + 0.001% formic acid.Eluent B: ACN. Column: Acquity CSH 1.7 μm 2.1 × 50 mm - 50° C.) MS m/z187.0746 54: (Z)-4-chloro-N′-hydroxy- HRMS(B) tR = 1.35 min; MS m/z2-(trifluoromethyl) benzimidamide 238.0121 55: (Z)-N′-hydroxy-3- HRMS(B)tR = 1.36 min; MS m/z (trifluoromethyl)benzimidamide 204.0510 56:(Z)-N′-hydroxy-4- HRMS(B) tR = 1.69 min; MS m/z(trifluoromethoxy)benzimidamide 220.0460 57: (Z)-4-fluoro-N′-hydroxy-HRMS(B) tR = 1.55 min; MS m/z 3-(trifluoromethoxy) benzimidamide238.0365 58: (Z)-3-(difluoromethoxy)-N′- HRMS(B) tR = 1.05 min; MS m/zhydroxybenzimidamide 202.0554 59: (Z)-4-chloro-N′-hydroxy-3- HRMS(B) tR= 1.14 min; MS m/z methoxybenzimidamide 200.0352 60:(Z)-4-chloro-N′-hydroxy- HRMS(B) tR = 1.19 min; MS m/z3-(trifluoromethyl) benzimidamide 239.3000 (M + H) 61:(Z)-3-(tert-butyl)-N′- HRMS(B) tR = 1.51 min ; MS m/zhydroxybenzimidamide 193.1342 (M + H) 62: (Z)-N′-hydroxy-1-methyl-HRMS(B) tR = 1.03 min; MS m/z 1H-indole-6-carboximidamide 190.0883 (M +H) 63: (Z)-N′-hydroxy-2,3- HRMS(B) tR = 1.30 min; MS m/zdihydro-1H-indene-5- 176.0950 carboximidamide 64: 4-chloro-N′- MS m/z171.0 (M + H)⁺; hydroxybenzimidamide Rt-0.35 min.

Intermediate 65: (S)-tert-butyl1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylcarbamate

A solution of 4-chloro-N′-hydroxybenzimidamide (1.24 g, 7.27 mmol),(S)-2-(tert-butoxycarbonylamino)propanoic acid (1.38 g, 7.27 mmol, 1.0equiv), and DCC (1.65 g, 8.00 mmol, 1.1 equiv) in 1,4-dioxane (73 mL)was heated at 100° C. for 18 hours. The reaction was then cooled to roomtemperature and concentrated in vacuo. Silica gel column chromatography(EtOAc/Heptane, 0 to 35%) provided (S)-tert-butyl1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylcarbamate (1.13 g, whitesolid) in 48% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, J=8.8 Hz, 2H),7.47 (d, J=8.8 Hz, 2H), 5.18 (m, 1H), 1.64 (d, J=6.8 Hz, 3H), 1.47 (s,9H).

Intermediate 66 (S)-tert-butyl(1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate

To a stirred solution of(Z)-3-chloro-N′-hydroxy-4-(trifluoromethoxy)benzimidamide (500 mg, 1.964mmol) and (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (372 mg,1.964 mmol) was added N,N′-methanediylidenedicyclohexanamine (1.1 eq,446 mg, 2.160 mmol) and allowed to reflux at 100° C. for 12 hours.Concentrate in vacuo, dilute w/ EtOAc, filter washing w/ EtOAc, wash w/water, brine, concentrate in vacuo. Flash column chromatography (silica,80 g) eluting w/ 0-5% EtOAc/DCM afforded 230 mg. HRMS m/z 407.0860

The intermediates in Table 3a were prepared using a method similar tothat described for the preparation of Intermediate 66

TABLE 3a

Intermediate 67

Intermediate 68

Intermediate 69

Intermediate 70

Intermediate 71

Intermediate 72

Intermediate 73

Intermediate 74

Intermediate 75

Intermediate 76

Intermediate 77

Intermediate 78

Intermediate 79

Intermediate 80

Intermediate 81

Intermediate 82

Intermediate 83

Intermediate 84

Intermediate 85

TABLE 3b Chemical name and analytical data for each intermediate listedin Table 3a. Intermediate: Name Analytical data 67: (S)-tert-butyl(1-(3-(4-bromo-3- HRMS(C) tR = 1.20 min; methoxyphenyl)-1,2,4-oxadiazol-MS m/z 397.0637 5-yl)ethyl)carbamate 68: (S)-tert-butyl(1-(3-(4-chloro-3- HRMS(C) tR = 1.42 min;methylphenyl)-1,2,4-oxadiazol-5- MS m/z 337.1193 yl)ethyl)carbamate 69:(S)-tert-butyl (1-(3-(1,2-dimethyl- HRMS(C) tR = 1.12 min;1H-indol-4-yl)-1,2,4-oxadiazol- MS m/z 356.1848 5-yl)ethyl)carbamate 70:(S)-tert-butyl (1-(3-(2- HRMS(C) tR = 1.12 min;(trifluoromethoxy)phenyl)-1,2,4- MS m/z 373.1249oxadiazol-5-yl)ethyl)carbamate 71: (S)-tert-butyl(1-(3-(2,2- HRMS(C) tR= 1.41 min; difluorobenzo[d][1,3]dioxol-5-yl)- MS m/z 369.11361,2,4-oxadiazol-5-yl)ethyl)carbamate 72: (S)-tert-butyl(1-(3-(3-(2,2,2-HRMS(C) tR = 1.33 min; trifluoroethoxy)phenyl)-1,2,4- MS m/z 387.1406oxadiazol-5-yl)ethyl)carbamate 73: (S)-tert-butyl(1-(3-(isoquinolin-8-yl)- HRMS(C) tR = 0.71 min;1,2,4-oxadiazol-5-yl)ethyl)carbamate MS m/z 340.1535 74:(S)-tert-butyl(1-(3-(4-chloro-2- HRMS(C) tR = 1.35 min;(trifluoromethyl)phenyl)-1,2,4- MS m/z 392.1055oxadiazol-5-yl)ethyl)carbamate 75: (S)-tert-butyl (1-(3-(3- HRMS(C) tR =1.41 min; (trifluoromethyl)phenyl)-1,2,4- MS m/z 357.1300oxadiazol-5-yl)ethyl)carbamate 76: (S)-tert-butyl(1-(3-(4-fluoro-3-HRMS(C) tR = 1.42 min; (trifluoromethoxy)phenyl)-1,2,4- MS m/z 392.1302oxadiazol-5-yl)ethyl)carbamate 77: (S)-tert-butyl (1-(3-(4- HRMS(C) tR =1.59 min; (trifluoromethyl)phenyl)-1,2,4- MS m/z 357.1300oxadiazol-5-yl)ethyl)carbamate 78: (S)-tert-butyl (1-(3-(3- HRMS(C) tR =1.38 min; (trifluoromethoxy)phenyl)-1,2,4- MS m/z 374.1378 (M + H)oxadiazol-5-yl)ethyl)carbamate 79: (S)-tert-butyl (1-(3-(4- HRMS(C) tR =1.69 min; (trifluoromethoxy)phenyl)-1,2,4- MS m/z 373.1249oxadiazol-5-yl)ethyl)carbamate 80: (S)-tert-butyl (1-(3-(3- HRMS(C) tR =1.12 min; (difluoromethoxy)phenyl)-1,2,4- MS m/z 355.1344oxadiazol-5-yl)ethyl)carbamate 81: (S)-tert-butyl (1-(3-(4-chloro-3-HRMS(C) tR = 1.14 min; methoxyphenyl)-1,2,4- MS m/z 353.1142oxadiazol-5-yl)ethyl)carbamate 82: (S)-tert-butyl(1-(3-(4-chloro-3-HRMS(C) tR = 1.52 min; (trifluoromethyl)phenyl)-1,2,4- MS m/z 391.0911oxadiazol-5-yl)ethyl)carbamate 83: (S)-tert-butyl (1-(3-(1-methyl-HRMS(C) tR = 1.03 min; 1H-indol-6-yl)-1,2,4-oxadiazol- MS m/z 342.16925-yl)ethyl)carbamate 84: (S)-tert-butyl (1-(3-(3-(tert- HRMS(C) tR =1.62 min; butyl)phenyl)-1,2,4-oxadiazol- MS m/z 345.20525-yl)ethyl)carbamate 85: (S)-tert-butyl (1-(3-(2,3- HRMS(C) tR = 1.50min; dihydro-1H-inden-5-yl)-1,2,4- MS m/z 329.1740oxadiazol-5-yl)ethyl)carbamate

Intermediate 86: (S)-tert-butyl (1-(5-bromopyridin-2-yl)ethyl)carbamate

To a solution of (S)-1-(5-bromopyridin-2-yl)ethanamine (300 mg, 1.49mmol) in DCM (7.5 mL) was added di-tert-butyl dicarbonate (358 mg, 1.64mmol) and triethylamine (0.31 mL, 2.24 mmol). The solution was stirredfor 16 h at room temperature then washed with water and brine. Theorganic layer was dried over Na2SO4, filtered and concentrated. Silicagel column chromatography (EtOAc/heptane 0 to 80%) provided a whitesolid (308 mg, 68.5% yield). ¹H NMR (400 MHz, CDCl3) δ 8.59 (d, J=2.2Hz, 1H), 7.76 (dd, J=8.3, 2.4 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 5.57-5.42(m, 1H), 4.86-4.73 (m, 1H), 1.43 (t, J=3.4 Hz, 12H); MS m/z 303.4 (M+H).

The intermediates in Table 4a were prepared using a method similar tothat described for the preparation of Intermediate 86

TABLE 4a

Intermediate 87

Intermediate 88

Intermediate 89

Intermediate 90

Intermediate 91

TABLE 4b Chemical name and analytical data for each intermediate listedin Table 4a. Intermediate: Name Analytical data 87: (S)-tert-butyl(1-(6-bromo- ¹H NMR (400 MHz, CDCl3) δ 8.33 pyridin-3-yl)ethyl)carbamate(d, J = 2.6 Hz, 1H), 7.49 (dd, J = 8.2, 2.5 Hz, 1H), 7.44 (d, J = 8.3Hz, 1H), 4.88-4.69 (m, 2H), 1.45 (d, J = 7.1 Hz, 3H), 1.41 (s, 9H); MSm/z 303.4 (M + H). 88: (S)-tert-butyl (1-(5-bromo-4- LCMS tR = 1.31 min;MS m/z 317.0 methylpyridin-2-yl)ethyl)carbamate (M + H) 89:(S)-tert-butyl (1-(5-bromo-6- LCMS tR = 1.35 min; MS m/z 317.1methylpyridin-2-yl)ethyl)carbamate (M + H) 90: (S)-tert-butyl(1-(5-bromo-3- LCMS tR = 1.31 min; MS m/z 319.0fluoropyridin-2-yl)ethyl)carbamate (M + H) 91: (S)-tert-butyl(1-(5-bromo-3- LCMS tR = 1.37 min; MS m/z 317.0methylpyridin-2-yl)ethyl)carbamate (M + H)

Intermediate 92: (S)-tert-butyl(1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)carbamate

In a 5 mL microwave vial a solution of (S)-tert-butyl(1-(5-bromopyridin-2-yl)ethyl)carbamate (60 mg, 0.2 mmol),(4-fluoro-3-methylphenyl)boronic acid (37 mg, 0.24 mmol), Sodiumbicarbonate (0.2 mL, 0.4 mmol, 2 M aqueous solution) in Dioxane (2 mL)was bubbled N2 for 3 min then Cl2Pd(dppf)CH2Cl2 (16 mg, 0.02 mmol) wasadded. The capped tube was heated to 100° C. for 16 h. After cooling thereaction mixture was diluted with EtOAc (10 mL) and washed with water(10 mL). After separation, the aqueous phase was extracted with EtOAc(3×10 mL). Combined organics were dried over Na2SO4, filtered andconcentrated. The crude material was purified through silica gel columnchromatography (EtOAc in Heptane 12 to 100%) to give a white solid (66mg, 80% yield). LCMS tR=1.43 min; MS m/z 331.1 (M+H).

The intermediates in Table 5a were prepared using a method similar tothat described for the preparation of Intermediate 92

TABLE 5a

Intermediate 93

Intermediate 94

Intermediate 95

Intermediate 96

Intermediate 97

Intermediate 98

Intermediate 99

Intermediate 100

Intermediate 101

Intermediate 102

Intermediate 103

Intermediate 104

Intermediate 105

TABLE 5b Chemical name and analytical data for each intermediate listedin Table 5a. Intermediate: Name Analytical data 93: (S)-tert-butyl(1-(5-(3-(trifluoromethyl)phenyl)pyridin- LCMS tR = 1.69 min; MS m/z365.5 (M − 2-yl)ethyl)carbamate H). 94: (S)-tert-butyl(1-(6-(4-fluoro-3-methylphenyl)pyridin- LCMS tR = 1.62 min; MS m/z 329.5(M − 3-yl)ethyl)carbamate H). 95: (S)-tert-butyl(1-(6-(3-(trifluoromethyl)phenyl)pyridin- LCMS tR = 1.68 min; MS m/z365.4 (M − 3-yl)ethyl)carbamate H). 96: (S)-tert-butyl(1-(2′-(trifluoromethyl)-[3,4′- ¹H NMR (400 MHz, CDCl3) δ 8.83 (t, J =bipyridin]-6-yl)ethyl)carbamate 3.9 Hz, 2H), 7.92 (dd, J = 8.3, 2.5 Hz,1H), 7.87 (d, J = 1.7 Hz, 1H), 7.73-7.66 (m, 1H), 7.42 (d, J = 8.1 Hz,1H), 5.59 (d, J = 7.6 Hz, 1H), 4.93 (p, J = 6.9 Hz, 1H), 1.50 (d, J =7.0 Hz, 3H), 1.45 (s, 9H); MS m/z 368.2 (M + H). 97: (S)-tert-butyl(1-(6′-(trifluoromethyl)-[2,3′- ¹H NMR (400 MHz, CDCl3) δ 9.27 (d, J =bipyridin]-5-yl)ethyl)carbamate 2.1 Hz, 1H), 8.71 (s, 1H), 8.49 (dd, J =8.3, 2.1 Hz, 1H), 7.80-7.75 (m, 3H), 4.90 (br s, 1H), 1.52 (d, J = 6.3Hz, 3H), 1.43 (s, 9H); MS m/z 368.2 (M + H). 98: (S)-tert-butyl(1-(6′-(trifluoromethyl)-[3,3′- ¹H NMR (400 MHz, CDCl3) δ 8.93 (d, J =bipyridin]-6-yl)ethyl)carbamate 2.1 Hz, 1H), 8.79 (d, J = 2.3 Hz, 1H),8.04 (dd, J = 8.2, 2.3 Hz, 1H), 7.88 (dd, J = 8.1, 2.4 Hz, 1H), 7.80 (d,J = 8.2 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 5.60 (d, J = 7.8 Hz, 1H),4.93 (p, J = 6.9 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H), 1.44 (s, 9H); MS m/z368.2 (M + H). 99: (S)-tert-butyl (1-(6-(trifluoromethyl)-[2,3′- ¹H NMR(400 MHz, CDCl3) δ 9.15 (d, J = bipyridin]-6′-yl)ethyl)carbamate 2.3 Hz,1H), 8.36 (dd, J = 7.8, 2.4 Hz, 1H), 8.01-7.89 (m, 2H), 7.66 (dd, J =7.5, 1.1 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 5.69 (d, J = 7.9 Hz, 1 H),4.92 (p, J = 6.9 Hz, 1H), 1.49 (d, J = 6.8 Hz, 3H), 1.45 (s, 9H); MS m/z368.2 (M + H). 100: (S)-tert-butyl (1-(4-methyl-2′-(trifluoromethyl)- ¹HNMR (400 MHz, CDCl3) δ 8.83 (d, J =[3,4′-bipyridin]-6-yl)ethyl)carbamate 4.9 Hz, 1H), 8.36 (s, 1H), 7.66(s, 1H), 7.51-7.42 (m, 1H), 7.21 (s, 1H), 5.60 (d, J = 7.7 Hz, 1H), 4.87(p, J = 6.9 Hz, 1H), 2.30 (s, 3H), 1.48 (d, J = 6.9 Hz, 3H), 1.45 (s,9H); MS m/z 326.4 (M + H − 56). 101: (S)-tert-butyl(1-(2-methyl-2′-(trifluoromethyl)- ¹H NMR (400 MHz, CDCl3) δ 8.81 (d, J= [3,4′-bipyridin]-6-yl)ethyl)carbamate 5.0 Hz, 1H), 7.66 (s, 1H), 7.50(d, J = 7.9 Hz, 1H), 7.47 (dd, J = 4.9, 1.6 Hz, 1H), 7.20 (d, J = 7.8Hz, 1H), 5.75 (d, J = 7.5 Hz, 1H), 4.86 (p, J = 6.9 Hz, 1H), 2.51 (s,3H), 1.48 (d, J = 6.9 Hz, 3H), 1.46 (s, 9H); MS m/z 326.4 (M + H − 56).102: (S)-tert-butyl (1-(5-fluoro-2′-(trifluoromethyl)- ¹H NMR (400 MHz,CDCl₃) δ 8.85 (d, J = [3,4′-bipyridin]-6-yl)ethyl)carbamate 5.1 Hz, 1H),8.66 (s, 1H), 7.87-7.84 (m, 1H), 7.70-7.67 (m, 1H), 7.65 (dd, J = 9.8,1.9 Hz, 1H), 5.76 (d, J = 7.7 Hz, 1H), 5.31-5.23 (m, 1H), 1.47 (d, J =6.8 Hz, 3H), 1.45 (s, 9H); MS m/z 386.1 (M + H). 103: (S)-tert-butyl(1-(5-methyl-2′-(trifluoromethyl)- ¹H NMR (400 MHz, CDCl3) δ 8.81 (d, J= [3,4′-bipyridin]-6-yl)ethyl)carbamate 5.1 Hz, 1H), 8.68 (d, J = 2.2Hz, 1H), 7.88-7.85 (m, 1H), 7.71 (d, J = 1.7 Hz, 1H), 7.68 (dd, J = 5.0,1.7 Hz, 1H), 5.99 (d, J = 8.2 Hz, 1H), 5.13 (p, J = 6.7 Hz, 1H), 2.48(s, 3H), 1.45 (s, 9H), 1.42 (d, J = 6.6 Hz, 3H); MS m/z 382.2 (M + H).104: 1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2- ¹H NMR (400 MHz, CDCl3)δ 9.30 (d, J = yl)ethanone 1.5 Hz, 1H), 9.11 (d, J = 1.5 Hz, 1H), 8.39(s, 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.69 (t, J = 7.8 Hz,1H), 2.76 (s, 3H).); MS m/z 266.9 (M + H). 105:1-(5-(4-fluoro-3-methylphenyl)pyrazin-2- ¹H NMR (400 MHz, CDCl3) δ 9.24(d, J = yl)ethanone 1.5 Hz, 1H), 9.01 (d, J = 1.5 Hz, 1H), 7.97 (dd, J =7.3, 1.9 Hz, 1H), 7.89 (ddd, J = 7.6, 4.8, 2.3 Hz, 1H), 7.17 (t, J = 8.9Hz, 1H), 2.74 (s, 3H), 2.39 (d, J = 2.0 Hz, 3H); MS m/z 230.9 (M + H).

The following intermediates were prepared using a method similar to thatdescribed for the preparation of Intermediate 92

Intermediate 106:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2′-(tert-butyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.67 min; MS m/z 519.3 (M+H).

Intermediate 107:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2′-(1,1,1-trifluoro-2-methylpropan-2-yl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl3) δ 8.83 (d, J=2.2 Hz, 1H), 8.73 (d, J=5.1 Hz,1H), 8.23 (d, J=5.6 Hz, 1H), 7.90 (dd, J=8.1, 2.3 Hz, 1H), 7.68 (s, 1H),7.50 (d, J=5.8 Hz, 1H), 7.47-7.41 (m, 2H), 5.34 (p, J=6.9 Hz, 1H),4.81-4.72 (m, 1H), 4.64 (dd, J=9.3, 2.9 Hz, 1H), 4.45 (p, J=6.3 Hz, 1H),4.36 (t, J=9.0 Hz, 1H), 1.69 (s, 6H), 1.63 (d, J=6.9 Hz, 3H), 1.26 (s,9H), 1.04 (d, J=6.4 Hz, 3H); MS m/z 573.3 (M+H).

Intermediate 108:(S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-fluorobenzoic Acid

To a solution of (S)-4-(1-aminoethyl)-2-fluorobenzoic acid (5 g, 22.76mmol) in water (66 mL) and THF (66 mL) was added di-tert-butyldicarbonate (6.95 g, 31.9 mmol) and sodium carbonate (5.74 g, 68.3mmol). The solution was stirred for 16 h at room temperature then THFwas removed under reduced pressure. The aqueous solution was acidifiedwith 1N HCl to pH 3-4 and extracted with EtOAc (3×60 mL). Combinedorganics were dried over Na2SO4, filtered and concentrated to give awhite solid (1.94 g, 30.1% yield). The crude product was used to nextstep without further purification.

¹H NMR (400 MHz, MeOD) δ 7.89 (t, J=7.8 Hz, 1H), 7.20 (dd, J=8.2, 1.7Hz, 1H), 7.13 (dd, J=12.0, 1.6 Hz, 1H), 4.70 (d, J=7.1 Hz, 1H),1.47-1.35 (m, 12H); MS m/z 282.0 (M−H).

Intermediate 109: (S)-tert-butyl1-(3-fluoro-4-(methoxy(methyl)carbamoyl) phenyl)ethylcarbamate

A solution of (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-fluorobenzoicacid (1.416 g, 5 mmol), N,O-dimethylhydroxylamine hydrochloride (732 mg,7.5 mmol), HATU (2.85 g, 7.5 mmol) and DIPEA (3.49 mL, 20 mmol) in DMF(25 mL) was stirred at room temperature for 16 h. The reaction mixturewas diluted with EtOAc and washed with water. After separation, theaqueous phase was washed with EtOAc (2×75 mL). Combined organics weredried over Na2SO4, filtered and concentrated. Silica gel columnchromatography (EtOAc/heptane 12 to 100%) provided (S)-tert-butyl1-(3-fluoro-4-(methoxy(methyl)carbamoyl)phenyl)ethylcarbamate as a whitesolid (1.5 g, 92% yield).

¹H NMR (400 MHz, CDCl3) δ 7.40 (t, J=7.4 Hz, 1H), 7.13 (dd, J=7.8, 1.6Hz, 1H), 7.04 (dd, J=10.7, 1.6 Hz, 1H), 4.80 (br s, 1H), 3.56 (s, 3H),3.34 (s, 3H), 1.50-1.29 (m, 12H); MS m/z 327.1 (M+H).

Intermediate 110: (S)-tert-butyl1-(3-fluoro-4-formylphenyl)ethylcarbamate

To a cooled (0° C.) solution of (S)-tert-butyl1-(3-fluoro-4-(methoxy(methyl)carbamoyl)phenyl)ethylcarbamate (1.175 g,3.6 mmol) in THF (36 mL) was added a solution of LAH in THF (1.0 M, 18mL, 18 mmol) and the resulting mixture was stirred at 0° C. for 20 min.The reaction mixture was quenched by addition of a saturated Na2SO4solution until gas evolution ceased. The reaction mixture was extractedwith EtOAc (2×100 mL). Combined organics were dried over Na2SO4,filtered and concentrated. Silica gel column chromatography(EtOAc/heptane 12 to 100%) provided (S)-tert-butyl1-(3-fluoro-4-formylphenyl)ethylcarbamate as a white solid (760 mg, 79%yield).

¹H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 7.87-7.80 (m, 1H), 7.20 (dd,J=8.2, 1.3 Hz, 1H), 7.11 (dd, J=11.5, 1.4 Hz, 1H), 4.80 (br s, 1H), 1.45(br s, 12H); MS m/z 212.1 (M-56+H).

Intermediate 111: (S)-tert-butyl1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethylcarbamate

A solution of (S)-tert-butyl 1-(3-fluoro-4-formylphenyl)ethylcarbamate(267 mg, 1 mmol) and 1,2,2-trimethylpiperazine dihydrochloride (402 mg,2 mmol) in THF (5 mL) was stirred at room temperature for 1 h andtreated with sodium triacetoxyborohydride (848 mg, 4 mmol). Theresulting mixture was stirred at room temperature for 16 h. The reactionmixture was quenched with saturated aqueous solution of NaHCO3 (15 mL)and extracted with EtOAc (3×25 mL). Combined organics were dried overNa2SO4, filtered and concentrated. Silica gel column chromatography(MeOH/CH2Cl2 0 to 10%) provided (S)-tert-butyl1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethylcarbamateas a white solid (186 mg, 49% yield). ¹H NMR (400 MHz, CDCl3) δ 7.35 (t,J=7.7 Hz, 1H), 7.03 (dd, J=7.9, 1.9 Hz, 1H), 6.95 (dd, J=11.1, 1.8 Hz,1H), 4.77 (s, 1H), 3.49 (s, 2H), 2.56 (br s, 4H), 2.24 (br s, 5H), 1.42(br s, 12H), 1.04 (s, 6H); MS m/z 380.4 (M+H).

Intermediate 112: (S)-tert-butyl1-(4-((4,4-difluoropiperidin-1-yl)methyl)-3-fluorophenyl)ethylcarbamate

Following the procedure for intermediate 111: Title compound wasprepared from (S)-tert-butyl 1-(3-fluoro-4-formylphenyl)ethylcarbamateand 4,4-difluoropiperidine hydrochloride as a white solid. LCMS tR=1.63min; MS m/z 371.5 (M−H).

Intermediate 113:1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanone

A cloudy solution of 1-(5-bromopyrimidin-2-yl)ethanone (300 mg, 1.49mmol), 3-(trifluoromethyl)phenylboronic acid (567 mg, 2.98 mmol), K₃PO₄(950 mg, 4.48 mmol), DavePhos ligand[2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl] (59 mg, 0.15mmol), and Pd(OAc)₂ (17 mg, 0.075 mmol) in 6 mL toluene was heated at100° C. for 1 h. The mixture was cooled to room temperature, andfiltered through Celite. Filter cake was rinsed with 30 mL EtOAc. Thefiltrate was poured into 20 mL water. Layers were separated, and theaqueous was further extracted with EtOAc (20 mL). Combined organics werewashed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, filteredand concentrated directly onto silica gel. Column chromatography(10-100% EtOAc/heptane) gave 0.26 g1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanone as tan solid. MSm/z 267.1 (M+H)+. ¹H NMR (400 MHz, CDCl₃) δ 9.16 (s, 2H), 7.93-7.69 (m,4H), 2.87 (s, 3H).

The intermediates in Table 6a were prepared using a method similar tothat described for the preparation of Intermediate 113

TABLE 6a

Intermediate 114

Intermediate 115

Intermediate 116

Intermediate 117

Intermediate 118

Intermediate 119

Intermediate 120

Intermediate 121

Intermediate 122

Intermediate 123

Intermediate 124

TABLE 6b Chemical name and analytical data for each intermediate listedin Table 6a, using Anal. RP-HPLC Column = Inertsil C8 Column, 3.0 μm,3.0 × 30 mm. Column Temperature = 50° C. Eluents = A: Water (5 mMAmmonium formate, 2% ACN); B: ACN. Flow Rate = 2 mL/min. Gradient = 0min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.)Intermediate: Name Analytical data 114: 1-(5-(3,4-dichlorophenyl)pyrimidin-2- Anal. RP-HPLC tR = 1.17 min. MS m/z 266.9 yl)ethanone. (M +H)+. 115: 1-(5-(4-fluoro-3-(trifluoromethyl)phenyl) Anal. RP-HPLC tR =1.26 min. MS m/z 285.2 pyrimidin-2-yl)ethanone. (M + H)+. 116:1-(5-(4-chloro-3-(trifluoromethyl)phenyl) Anal. RP-HPLC tR = 1.33 min.MS m/z 301.3 pyrimidin-2-yl)ethanone. (M + H)+. 117::1-(5-(5-fluoro-2-methylphenyl) Anal. RP-HPLC tR = 1.16 min. MS m/z 231.2pyrimidin-2-yl)ethanone (M + H)+. 118: 1-(5-(4-fluoro-3-methylphenyl)pyrimidin- ¹H NMR (400 MHz, CDCl₃) δ 9.09 (s, 2H), 2-yl)ethanone.7.52-7.41 (m, 2H), 7.24-7.16 (m, 1H), 2.85 (s, 3H), 2.41 (d, J = 2.0 Hz,3H). Anal. RP- HPLC tR = 1.20 min. MS m/z 231.0 (M + H)+. 119:1-(5-(2,3-dichlorophenyl) pyrimidin-2- Anal. RP-HPLC tR = 1.15 min. MSm/z 267.9 yl)ethanone (M + H)+. 120: 1-(5-(4-fluoro-3-methylphenyl)pyridin-2- ¹H NMR (400 MHz, CDCl₃) δ 8.88 (dd, J = 2.3, yl)ethanone. 0.8Hz, 1H), 8.13 (dd, J = 8.1, 0.8 Hz, 1H), 7.98 (dd, J = 8.1, 2.3 Hz, 1H),7.50-7.39 (m, 2H), 7.21-7.12 (m, 1H), 2.78 (s, 3H), 2.42- 2.36 (m, 3H).Anal. RP-HPLC tR = 1.40 min. MS m/z 230.8 (M + H)+. 121:1-(5-(2-fluoro-3-(trifluoromethyl)phenyl) Anal. RP-HPLC tR = 1.19 min.MS m/z 285.0 pyrimidin-2-yl)ethanone. (M + H)+. 122:1-(5-(4-chloro-3-methylphenyl) Anal. RP-HPLC tR = 1.30 min. MS m/z 247.2pyrimidin-2-yl)ethanone. (M + H)+. 123:1-(5-(3-chloro-5-(trifluoromethyl)phenyl) Anal. RP-HPLC tR = 1.27 min.MS m/z 301.0 pyrimidin-2-yl)ethanone. (M + H)+. 124:1-(5-(4-(trifluoromethyl)phenyl) Anal. RP-HPLC tR = 1 .22 min. MS m/z266.8 pyrimidin-2-yl)ethanone. (M + H)+.

Intermediate 125:(S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine

2,2,2-Trifluoroacetic acid (4 mL, 52 mmol) was added to a solution of(S)-tert-butyl 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylcarbamate(0.613 g, 1.89 mmol) in DCM (10 mL) at room temperature. The solutionwas stirred at room temperature for 1 hour and then concentrated invacuo. The residue was dissolved in chloroform (100 mL) and washed withsaturated aqueous sodium bicarbonate (100 mL). The layers were separatedand the aqueous layer was extracted with chloroform (3×30 mL) and thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give(S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine (500 mg,yellow oil). The material was used without further purification. ¹H NMR(400 MHz, CDCl₃) δ 8.04 (d, J=8.7 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 4.37(q, J=6.9 Hz, 1H), 1.62 (d, J=6.9 Hz, 3H). MS m/z 224.0 (M+H)⁺; Rt-0.56min.

Intermediate 126(S)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethanamine

(S)-tert-butyl(1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate(2.0 g, 4.90 mmol) was treated with 90% TFA/water for 2 hours.Concentrate in vacuo and neutralized by passing through a column ofMP-carbonate resin (6.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOHafforded 1.4 g waxy off-white solid. HRMS m/z 307.0335

Intermediate 127(S)-1-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine

To a stirred solution of(S)-2-(1-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)isoindoline-1,3-dione(100 mg, 0.283 mmol) in ethanol (5 ml) was added methylhydrazine (16 μL,0.311 mmol). Stir for 13 hours at 80° C. Concentrate in vacuo. Flashcolumn chromatography (silica, 40 g) eluting with dichloromethaneafforded 50 mg of desired product. HRMS m/z 224.4 (M+H)

The intermediates in Table 7a were prepared using a method similar tothat described for the preparation of Intermediate 126 or Intermediate127

TABLE 7a

Intermediate 128

Intermediate 129

Intermediate 130

Intermediate 131

Intermediate 132

Intermediate 133

Intermediate 134

Intermediate 135

Intermediate 136

Intermediate 137

Intermediate 138

Intermediate 139

Intermediate 140

Intermediate 141

Intermediate 142

Intermediate 143

Intermediate 144

Intermediate 145

Intermediate 146

Intermediate 147

Intermediate 148

TABLE 7b Chemical name and analytical data for each intermediate listedin Table 7a. Intermediate: Name Analytical data 128:(S)-1-(3-(4-bromo-3-methoxyphenyl)-1,2,4-oxadiazol-5- HRMS(B) tR = 1.88min; yl)ethanamine m/z 297.0113 129:(S)-1-(3-(4-chloro-3-methylphenyl)-1,2,4-oxadiazol-5- HRMS(B) tR = 2.05min; yl)ethanamine m/z 237.0669 130:(S)-1-(3-(1,2-dimethyl-1H-indol-4-yl)-1,2,4-oxadiazol-5- HRMS(B) tR =1.38 min; yl)ethanamine m/z 256.1324 131:(S)-1-(3-(2-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5- HRMS(B) tR =1.92 min; yl)ethanamine m/z 273.0725 132:(S)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol- HRMS(B)tR = 2.04 min; 5-yl)ethanamine m/z 269.0612 133:(S)-1-(3-(3-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-oxadiazol-5- HRMS(B) tR= 2.02 min; yl)ethanamine m/z 287.0882 134:(S)-1-(3-(isoquinolin-8-yl)-1,2,4-oxadiazol-5-yl)ethanamine HRMS(B) tR =0.68 min; m/z 240.1011 135:(S)-1-(3-(4-chloro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol- HRMS(B)tR = 2.08 min; 5-yl)ethanamine m/z 291.0386 136:(S)-1-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5- HRMS(B) tR =2.02 min; yl)ethanamine m/z 257.0776 137:(S)-1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5- HRMS(B) tR =2.01 min; yl)ethanamine m/z 257.0776 138:(S)-1-(3-(3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5- HRMS(B) tR =1.20 min; yl)ethanamine m/z 274.0 (M + H) 139:(S)-1-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5- HRMS(B) tR =2.09 min; yl)ethanamine m/z 273.0725 140:(S)-1-(3-(4-fluoro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol- HRMS(B)tR = 2.16 min; 5-yl)ethanamine m/z 291.0631 141:(S)-1-(3-(isoquinolin-8-yl)-1,2,4-oxadiazol-5-yl)ethanamine HRMS(B) tR =0.71 min; m/z 240.1011 142:(S)-1-(3-(1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5- HRMS(B) tR = 1.67min; yl)ethanamine m/z 242.1168 143:(S)-1-(3-(3-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5- HRMS(B) tR =1.74 min; yl)ethanamine m/z 255.0819 144:(S)-1-(3-(4-chloro-3-methoxyphenyl)-1,2,4-oxadiazol-5- HRMS(B) tR = 1.82min; yl)ethanamine m/z 253.0618 145:(S)-1-(3-(4-chloro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol- HRMS(B)tR = 2.26 min; 5-yl)ethanamine m/z 291.0386 146:(S)-1-(3-(1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5- HRMS(B) tR = 1.67min; yl)ethanamine m/z 242.1168 147:(S)-1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethanamine HRMS(B)tR = 2.33 min; m/z 246.1552 148:(S)-1-(3-(2,3-dihydro-1H-inden-5-yl)-1,2,4-oxadiazol-5- HRMS(B) tR =2.02 min; yl)ethanamine m/z 229.1215

Intermediate 149:1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanamine

1-(5-(3-(Trifluoromethyl)phenyl)pyrimidin-2-yl)ethanone (260 mg, 0.977mmol), NH4OAc (1.13 g, 14.6 mmol), and NaBH3CN (245 mg, 3.91 mmol) weretaken up in 8 mL 200 proof EtOH, and heated at 120° C. for 5 minutes ina microwave apparatus. The mixture was concentrated to remove the EtOH.Crude was taken up in 30 ml water+25 mL EtOAc. 6N NaOH was added untilaqueous pH was ˜10. Separated layers, and extracted aqueous with EtOAc(25 ml). The combined organic layer was washed with 25 mL brine anddried with Na₂SO₄. Filtered and concentrated with reduced pressure togive 262 mg crude yellow oil, which was carried forward without furtherpurification. Anal. RP-HPLC tR=0.90 min. (Column=Inertsil C8 Column, 3.0μm, 3.0×30 mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammoniumformate, 2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 268.1 (M+H)+.

The intermediates in Table 8a were prepared using a method similar tothat described for the preparation of Intermediate 149

TABLE 8a

Intermediate 150

Intermediate 151

Intermediate 152

Intermediate 153

Intermediate 154

Intermediate 155

Intermediate 156

Intermediate 157

Intermediate 158

Intermediate 159

Intermediate 160

Intermediate 161

Intermediate 162

TABLE 8b Chemical name and analytical data for each intermediate listedin Table 8a. Intermediate: Name Analytical data 150:1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethanamine. Anal. RP-HPLC tR =1.09 min; MS m/z 268.4 (M + H)+. 151:1-(5-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2- Anal. RP-HPLC tR =1.04 min. MS yl)ethanamine. m/z 286.3 (M + H)+. 152:1-(5-(4-chloro-3-(trifluoromethyl)phenyl)pyrimidin-2- Anal. RP-HPLC tR =1.06 min. MS yl)ethanamine. m/z 302.3 (M + H)+. 153:1-(5-(5-fluoro-2-methylphenyl)pyrimidin-2- Anal. RP-HPLC tR = 0.79 min.MS yl)ethanamine m/z 232.0 (M + H)+. 154:1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2- Anal. RP-HPLC tR = 0.81 min.MS yl)ethanamine m/z 231.9 (M + H)+. 155:1-(5-(2,3-dichlorophenyl)pyrimidin-2-yl)ethanamine Anal. RP-HPLC tR =1.01 min. MS m/z 269.0 (M + H)+. 156:1-(5-(4-fluoro-3-methylphenyl)pyridin-2- Anal. RP-HPLC tR = 0.92 min. MSyl)ethanamine m/z 230.9 (M + H)+. 157:1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2- Anal. RP-HPLC tR =0.96 min. MS yl)ethanamine. m/z 286.0 (M + H)+. 158:1-(5-(4-chloro-3-methylphenyl)pyrimidin-2- Anal. RP-HPLC tR = 0.97 min.MS yl)ethanamine. m/z 247.9 (M + H)+. 159:1-(5-(3-chloro-5-(trifluoromethyl)phenyl)pyrimidin-2- Anal. RP-HPLC tR =1.06 min. MS yl)ethanamine. m/z 301.9 (M + H)+. 160:1-(5-(4-(trifluoromethyl)phenyl)pyrimidin-2- Anal. RP-HPLC tR = 1.02min. MS yl)ethanamine. m/z 268.2 (M + H)+. 161:1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2- LCMS tR = 1.04 min; MS m/zyl)ethanamine 267.9 (M + H)+. 162:1-(5-(4-fluoro-3-methylphenyl)pyrazin-2- LCMS tR = 0.91 min; MS m/zyl)ethanamine 231.9 (M + H)+.

Intermediate 163: 1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethanamine

Step 1: A solution of 1-(5-fluoropyrimidin-2-yl)ethanone (700 mg, 5.0mmol) and 4-fluorophenol (616 mg, 5.50 mmol) in 6 mL DMF was treatedwith potassium carbonate (829 mg 6.0 mmol) and heated to 50° C. for 3.5h. The reaction mixture was poured into 20 mL water, and extracted withEtOAc (2×20 mL). Organics were washed with 20 mL each water, brine, anddried over Na₂SO₄. Mixture was filtered and concentrated on silica gel.Column chromatography (10-100% EtOAc/hept) gave 295 mg (25%)1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethanone as a white solid useddirectly in the following step. MS m/z 233.2 (M+H)+. ¹H NMR (400 MHz,CDCl₃) δ 8.55 (s, 2H), 7.23-7.07 (m, 4H), 2.78 (s, 3H).

Step 2: 1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethanone (290 mg, 1.25mmol), NH4OAc (1.9 g, 24.6 mmol), and NaBH₃CN (314 mg, 5.00 mmol) weretaken up in 20 mL 200 proof EtOH, and heated at 130 C for 3 minutes in amicrowave apparatus. The mixture was concentrated to remove the EtOH.Crude was taken up in 30 ml water+25 mL EtOAc. 6N NaOH was added untilaqueous pH was ˜10. Separated layers, and extracted aqueous with EtOAc(25 ml). The combined organic layer was washed with 25 mL brine anddried with Na₂SO₄. Filtered and concentrated with reduced pressure togive 275 mg crude tan oil, which was carried forward without furtherpurification. Major product Anal. RP-HPLC tR=1.26 min. (Column=InertsilC8 Column, 3.0 μm, 3.0×30 mm. Column Temperature=50° C. Eluents=A: Water(5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z234.1 (M+H)+.

Intermediate 164:1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanamine

Step 1: In a well vented vial, 90% t-butyl nitrite (4.74 mL, 35.8 mmol)and CuCl (2.96 g, 29.9 mmol) were taken up in 30 mL ACN. Over 15 mins,4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-amine(6.0 g, 19.9 mmol) was added in portions. Gas evolved. The mixture wasstirred 30 min at r.t., then warmed to 65 C for another 30 min.

The reaction mixture was filtered through Celite. 200 mL Water was addedto the filtrate. This was extracted with (2×150 mL) EtOAc. Organics werewashed with 200 mL brine, and dried over Na2SO4. Filtered andconcentrated on silica gel. Flash column chromatography (10-50% EA/hept)gave 3.35 g (52%)2-chloro-4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazoleas a green oil. MS m/z 321.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.69 (dd,J=5.1, 0.8 Hz, 1H), 7.52 (dq, J=1.7, 0.8 Hz, 1H), 7.31-7.22 (m, 1H),2.55 (s, 3H), 1.67 (s, 6H).

Step 2: To a solution of2-chloro-4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole(3.3 g, 10.3 mmol) and Pd(PPh3)2Cl2 (0.72 g, 1.03 mmol) in 50 mL dioxaneunder nitrogen, tributyl(1-ethoxyvinyl)stannane (3.82 ml, 11.32 mmol)was added. The mixture was heated to 100 C for 16 h. The reaction wascooled to r.t. and diluted with 25 mL EtOAc. 2M KF (15.4 ml) solutionwas added and stirred for 1 h. Copious precipitate formed. The reactionwas filtered through Celite and chased with EtOAc. The organic layer wasrinsed with 60 mL water, and concentrated to give grey solid. Crudesolid was dissolved in THF (50 mL) and 1N HCl (20.58 mL) was added. Thereaction was stirred at r.t. for 2 h. The mixture was neutralized byaddition of 1 N NaOH. THF was removed in vacuo. Extracted aqueous with2×50 mL EtOAc. The organic layers were washed with 50 mL brine, anddried over Na2SO4. Filtered and concentrated on silica gel. Flashchromatography using 10-50% EtOAc in heptane gave 1.65 g (49%)1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanoneas a yellow oil. MS m/z 329.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.72(dd, J=5.2, 0.9 Hz, 1H), 7.60 (dq, J=1.8, 0.9 Hz, 1H), 7.34 (dd, J=5.1,1.6 Hz, 1H), 2.74 (s, 3H), 2.63 (s, 3H), 1.69 (s, 6H).

Step 3:1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanoneethanone (1.6 g, 4.87 mmol), NH4OAc (5.6 g, 73.1 mmol), and NaBH3CN (1.2g, 19.5 mmol) were taken up in 40 mL 200 proof EtOH, and heated at 130 Cfor 10 minutes in a sealed tube. The mixture was concentrated to removethe EtOH. Crude was taken up in 50 ml water+50 mL EtOAc. 6N NaOH wasadded until aqueous pH was ˜9. Separated layers, and extracted aqueouswith EtOAc (50 ml). The combined organic layer was washed with 60 mLbrine and dried with Na2SO4. Filtered and concentrated with reducedpressure to give 1.58 g crude tan oil. This material was taken up in 20mL dioxane. 2.2 eq HCl (4N in dioxane) was added, and stirred 1 h.Yellow ppt was formed. The suspension was concentrated in vacuo to give1.97 g1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanaminedihydrochloride salt as a yellow-green solid, which was carried forwardwithout further purification. Major product Anal. RP-HPLC tR=1.23 min.MS m/z 330.1 (M+H)+.

Intermediate 165: 4-((S)-1-Amino-ethyl)-piperidine-1-carboxylic AcidBenzyl Ester

Benzyl4-((1S)-1-(1,1-dimethylethylsulfinamido)ethyl)piperidine-1-carboxylate(1.825 g, 4.98 mmole) was dissolved in dioxane (10 mL) and 4N HCl indioxane (5 mL, 1.3 eq.) was added. The mixture was stirred for 3 hoursat room temperature. The solvents were removed by rotary evaporation togive the title compound as a hydrochloride salt (1.3 g). ¹H NMR (400MHz, CD2Cl2) δ 8.46 (s, 2H), 7.44-7.27 (m, 5H), 5.11 (s, 2H), 4.26 (d,J=13.57 Hz, 2H), 3.24-3.12 (m, 1H), 2.86-2.61 (m, 2H), 1.99-1.86 (m,3H), 1.38 (d, J=6.33 Hz, 3H), 1.34-1.23 (m, 2H). HRMS(C) tR=1.87 min; MSm/z 263.1760 (M+H)+

Intermediate 166:(S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethanamine

To a solution of (S)-tert-butyl(1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)carbamate (66 mg, 0.47mmol) in DCM (2 mL) was added TFA (2 mL, 26 mmol) slowly at −78° C. Thereaction was stirred at room temperature for 1 h then concentrated anddiluted with DCM (10 mL). The solution was stirred with 3 eq. ofMP-carbonate resin (3.28 mmol/g, Biotage) for 1 hr at room temperature.The resin was removed by filtration and washed (2×5 mL) with DCM. Thefiltrate was concentrated and the crude residue was used to next stepwithout further purification. LCMS tR=0.97 min; MS m/z 231.1 (M+H).

The intermediates in Table 9a were prepared using a method similar tothat described for the preparation of Intermediate 166

TABLE 9a

Intermediate 167

Intermediate 168

Intermediate 169

Intermediate 170

Intermediate171

Intermediate 172

Intermediate 173

Intermediate 174

Intermediate 175

Intermediate 176

Intermediate 177

Intermediate 178

Intermediate 179

TABLE 9b Chemical name and analytical data for each intermediate listedin Table 9a. Intermediate: Name Analytical data 167:(S)-1-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethanamine LCMS tR =1.12 min; MS m/z 267.7 (M + H). 168:(S)-1-(6-(4-fluoro-3-methylphenyl)pyridin-3-yl)ethanamine LCMS tR= 1.05min; MS m/z 231.4 (M + H). 169:(S)-1-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)ethanamine LCMS tR =1.14 min; MS m/z 267.4 (M + H). 170:(S)-1-(2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine LCMS tR =0.79 min; MS m/z 268.1 (M + H). 171:(S)-1-(6′-(trifluoromethyl)-[2,3′-bipyridin]-5-yl)ethanamine LCMS tR =0.81 min; MS m/z 268.1 (M + H). 172:(S)-1-(6′-(trifluoromethyl)-[3,3′-bipyridin]-6-yl)ethanamine LCMS tR =0.81 min; MS m/z 268.1 (M + H). 173:(S)-1-(6-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)ethanamine LCMS tR =0.89 min; MS m/z 268.1 (M + H). 174:(S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6- LCMS tR = 0.85min; MS yl)ethanamine m/z 282.1 (M + H). 175:(S)-1-(2-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6- LCMS tR = 0.86min; MS yl)ethanamine m/z 282.1 (M + H). 176:(S)-1-(5-fluoro-2′-(trifluoromethyl)-[3,4′-bipyridin]-6- LCMS tR = 0.88min; MS yl)ethanamine m/z 286.1 (M + H). 177:(S)-1-(5-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6- LCMS tR = 0.89min; MS yl)ethanamine m/z 282.1 (M + H). 178:(S)-1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1- LCMS tR = 0.29 min; MSyl)methyl)phenyl)ethanamine m/z 280.2 (M + H). 179:(S)-1-(4-((4,4-difluoropiperidin-1-yl)methyl)-3- LCMS tR = 0.29 min; MSfluorophenyl)ethanamine m/z 273.2 (M + H).

Intermediate 180: (S)-tert-butyl(1-hydrazinyl-1-oxopropan-2-yl)carbamate

A solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)propanoate (1.00g, 4.92 mmol) and hydrazine (0.23 mL, 1.5 equiv) in THF (8 mL) washeated in a sealed tube at 72° C. for 15 hours. Additional hydrazine(0.23 mL, 1.5 equiv) was added and heating was continued for another 21hours. The reaction was then cooled to room temperature and concentratedin vacuo to give crude (S)-tert-butyl(1-hydrazinyl-1-oxopropan-2-yl)carbamate (1 g, white solid), which wasused without purification. ¹H NMR (400 MHz, CDCl₃) δ 4.20 (m, 1H), 1.44(s, 9H), 1.36 (d, J=7.1 Hz, 3H).

Intermediate 181: (S)-tert-butyl(1-(2-(4-chlorobenzoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate

4-Chlorobenzoyl chloride (0.63 mL, 4.92 mmol, 1.0 equiv) was added to asolution of (S)-tert-butyl (1-hydrazinyl-1-oxopropan-2-yl)carbamate (1.0g, 4.92 mmol) in DCM (25 mL) at 0° C. A white precipitate formed. Themixture was stirred at 0° C. for 1 hour and the reaction mixture wasthen concentrated in vacuo to give crude (S)-tert-butyl(1-(2-(4-chlorobenzoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate (1.55 g),which was used without purification. ¹H NMR (400 MHz, CD₃OD) δ 7.85 (d,J=8.7 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H), 4.21 (q, J=7.0 Hz, 1H), 1.45 (s,9H), 1.41 (d, J=7.2 Hz, 3H). MS m/z 342.1 (M+H)⁺; Rt-0.69 min.

Intermediate 182: (S)-tert-butyl(1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)carbamate

A solution of (S)-tert-butyl(1-(2-(4-chlorobenzoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate (1.0 g,2.93 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane2,4-disulfide (1.18 g, 2.93 mmol, 1.0 equiv) in THF (29 mL) was heatedat reflux for 2 hours. The reaction wash then cooled to room temperatureand filtered through a pad of celite, using THF to wash through. Thefiltrate was concentrated in vacuo. Silica gel column chromatography(EtOAc/Heptane, 0 to 30%) provided (S)-tert-butyl(1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)carbamate (0.600 g,light green solid) in 60% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.89 (d,J=8.5 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 5.23 (m, 1H), 1.72 (d, J=6.5 Hz,3H), 1.48 (s, 9H). MS m/z 340.1 (M+H)⁺; Rt-0.99 min.

Intermediate 183:(S)-1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethanamine

A solution of hydrogen chloride (4.0 M in 1,4-dioxane, 4 mL, 16 mmol, 9equiv) was added to a solution of (S)-tert-butyl(1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)carbamate (600 mg,1.77 mmol) in 1,4-dioxane (5 mL) at room temperature. The solution wasstirred for 3 hours, by which time a white precipitate had formed. Thereaction was concentrated in vacuo to give the hydrochloride salt of(S)-1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethanamine (480 mg,white solid) in 97% yield. The material was used without purification.¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz,2H), 5.10 (q, J=6.9 Hz, 1H), 1.82 (d, J=6.9 Hz, 3H). MS m/z 240.0(M+H)⁺; Rt-0.54 min.

Intermediate 184: (S)-tert-butyl but-3-yn-2-ylcarbamate

A solution of (S)-tert-butyl (1-oxopropan-2-yl)carbamate (500 mg, 2.89mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (610 mg, 3.18 mmol, 1.1equiv), and potassium carbonate (638 mg, 4.62 mmol, 1.6 equiv) inmethanol (14.4 mL) was stirred at room temperature for 18 hours. Thereaction was then diluted with ethyl acetate (30 mL) and saturatedaqueous sodium chloride (40 mL). The layers were separated and theaqueous layer was extracted with ethyl acetate (30 mL) and the combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated.Silica gel column chromatography (20% EtOAc in Heptane) provided(S)-tert-butyl but-3-yn-2-ylcarbamate (0.258 g, white solid) in 53%yield. ¹H NMR (400 MHz, CDCl₃) δ 4.49 (m, 1H), 2.26 (d, J=2.2 Hz, 1H),1.46 (s, 9H), 1.41 (d, J=6.8 Hz, 3H).

Intermediate 185: (S)-tert-butyl(1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)carbamate

A solution of (S)-tert-butyl but-3-yn-2-ylcarbamate (250 mg, 1.48 mmol),1-azido-4-chlorobenzene (227 mg, 1.48 mmol, 1.0 equiv), andN-ethyl-N-isopropylpropan-2-amine (0.77 mL, 4.43 mmol, 3.0 equiv) inanhydrous acetonitrile (14.8 mL) was stirred at room temperature for 10min. Copper(I) iodide (563 mg, 2.95 mmol, 2.0 equiv) was then added inportions. The mixture was stirred at room temperature for 30 min. Thereaction was quenched with saturated aqueous ammonium chloride (50 mL)and diluted with water (50 mL). The mixture was extracted with ethylacetate (3×30 mL) and the combined organic extracts were washed withwater (30 mL), saturated aqueous sodium chloride (30 mL), dried overNa₂SO₄, filtered and concentrated. Silica gel column chromatography(EtOAc/Heptane) provided (S)-tert-butyl(1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)carbamate (0.428 g,white solid) in 90% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.86 (s, 1H), 7.68(d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 5.02 (m, 1H), 1.63 (d, J=6.8Hz, 3H), 1.46 (s, 9H). MS m/z 323.1 (M+H)⁺; Rt-0.92 min.

Intermediate 186:(S)-1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethanamine

A solution of hydrogen chloride (4.0 M in 1,4-dioxane, 3.3 mL, 13.2mmol, 10 equiv) was added to a solution of (S)-tert-butyl(1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)carbamate (425 mg,1.32 mmol) in 1,4-dioxane (5 mL) at room temperature. The solution wasstirred for 1 hour, by which time a white precipitate had formed. Thereaction was concentrated in vacuo to give the hydrochloride salt of(S)-1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethanamine (338 mg,white solid) in 99% yield. The material was used without purification.¹H NMR (400 MHz, CD₃OD) δ 8.68 (s, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.63 (d,J=9.0 Hz, 2H), 4.77 (q, J=6.9 Hz, 1H), 1.78 (d, J=6.9 Hz, 3H). MS m/z223.1 (M+H)⁺; Rt-0.50 min.

Intermediate 187: 2-(6-methylpyridin-3-yl)thiazole-5-carbaldehyde

A mixture of 2-bromothiazole-5-carbaldehyde (400 mg, 2.08 mmol),(6-methylpyridin-3-yl)boronic acid (428 mg, 3.12 mmol, 1.5 equiv),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (170 mg, 0.21 mmol, 0.1 equiv) and 2.0 M aqueoussodium carbonate (5.2 mL, 10.4 mmol, 5 equiv) in 1,2-dimethoxyethane(6.9 mL) was heated in a microwave reactor at 110° C. for 20 minutes.The reaction was then diluted with ethyl acetate (50 mL) and water (50mL). The layers were separated and the aqueous layer was extracted withethyl acetate (2×25 mL). The combined organic extracts were washed withsaturated aqueous sodium chloride (30 mL), dried over Na₂SO₄, filteredand concentrated. Silica gel column chromatography (EtOAc) provided2-(6-methylpyridin-3-yl)thiazole-5-carbaldehyde (0.176 g, brown solid)in 41% yield. ¹H NMR (400 MHz, CDCl₃) δ 10.08 (s, 1H), 9.15 (d, J=2.0Hz, 1H), 8.47 (s, 1H), 8.19 (dd, J=8.1, 2.4 Hz, 1H), 7.31 (d, J=8.3 Hz,1H), 2.66 (s, 3H). MS m/z 205.0 (M+H)⁺; Rt-0.36 min.

The intermediates in Table 10a were prepared using a method similar tothat described for the preparation of Intermediate 187

TABLE 10a

Intermediate 188

Intermediate 189

Intermediate 190

TABLE 10b Chemical name, NMR chemical shifts and LCMS signal for eachintermediate listed in Table 10a. Intermediate: Name ¹H NMR (400 MHz,CDCl₃) δ ppm LCMS 188: 2-(6-methylpyridin-3-yl)thiazole-5- 10.08 (s,1H), 9.15 (d, J = 2.0 MS m/z carbaldehyde Hz, 1H), 8.47 (s, 1H), 8.19(dd, 205.0 (M + H)⁺; J = 8.1, 2.4 Hz, 1H), 7.31 (d, J = Rt-0.36 min 8.3Hz, 1H), 2.66 (s, 3H). 189: 2-(6-(trifluoromethyl)pyridin-3- 10.13 (s,1H), 9.37 (d, J = 1.6 MS m/z yl)thiazole-5-carbaldehyde Hz, 1H), 8.55(s, 1H), 8.50 (dd, 259.0 (M + H)⁺; J = 8.2, 2.0 Hz, 1H), 7.85 (d, J =Rt-0.74 min 8.2 Hz, 1H) 190: 2-(2-(trifluoromethyl)pyridin-4- 10.14 (s,1H), 8.91 (d, J = 5.0 MS m/z yl)thiazole-5-carbaldehyde Hz, 1H), 8.57(d, J = 0.6 Hz, 259.0 (M + H)⁺; 1H), 8.30 (s, 1H), 8.06 (d, J = Rt-0.76min 5.1 Hz, 1H)

Intermediate 191: 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-1H-imidazole

A solution of ethane-1,2-diol (0.081 mL, 1.45 mmol, 1.5 equiv),1-(4-chlorophenyl)-1H-imidazole-4-carbaldehyde (200 mg, 0.968 mmol), andcamphorsulfonic acid (45 mg, 0.19 mmol, 0.2 equiv) in toluene (10 mL)was heated at reflux with a Dean-Stark apparatus for 1 hour. Thereaction was cooled to room temperature and quenched with saturatedaqueous sodium bicarbonate (30 mL). The mixture was extracted with ethylacetate (30 mL) and the organic layer was dried (Na₂SO₄), filtered, andconcentrated in vacuo. Silica gel column chromatography (EtOAc with 7%methanol) provided 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-1H-imidazole(0.100 g, tan solid) in 41% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.80 (s,1H), 7.46 (d, J=8.4 Hz, 2H), 7.36 (s, 1H), 7.33 (d, J=8.4 Hz, 2H), 5.96(s, 1H), 4.20 (m, 2H), 4.05 (m, 2H). MS m/z 251.0 (M+H)⁺; Rt-0.53 min.

Intermediate 192:1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-2-methyl-1H-imidazole

A solution of n-butyllithium (1.6 M in hexane, 0.37 mL, 0.60 mmol, 1.5equiv) was added to a solution of N,N-diisopropylamine (0.085 mL, 0.60mmol, 1.5 equiv) in THF (1.5 mL) at −78° C. The solution was stirred at−78° C. for 10 min and then a solution of1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-1H-imidazole (100 mg, 0.40mmol) in THF (1 mL) was added dropwise. The resulting solution wasstirred at −78° C. for 30 min, and then iodomethane (0.042 mL, 0.68mmol, 1.7 equiv) was added. The solution was allowed to warm to roomtemperature and then quenched with water (20 mL). The mixture wasextracted with ethyl acetate (30 mL) and the organic extract was washedwith saturated aqueous sodium chloride (15 mL), dried (Na₂SO₄),filtered, and concentrated in vacuo to give crude1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-2-methyl-1H-imidazole. Thematerial was used without further purification. ¹H NMR (400 MHz, CDCl₃)δ 7.46 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.09 (s, 1H), 5.88 (s,1H), 4.20 (m, 2H), 4.03 (m, 2H), 2.35 (s, 3H). MS m/z 265.0 (M+H)⁺;Rt-0.57 min.

Intermediate 193:1-(4-chlorophenyl)-2-methyl-1H-imidazole-4-carbaldehyde

A solution of1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-2-methyl-1H-imidazole (1.05 g,3.97 mmol) and camphorsulfonic acid (92 mg, 0.40 mmol, 0.1 equiv) in THF(26.5 mL) and water (13.3 mL) was heated at 60° C. for 1 hour. Thereaction was then cooled to room temperature and quenched with saturatedaqueous sodium bicarbonate (100 mL). The mixture was extracted withethyl acetate (100 mL) and the organic layer was washed with saturatedaqueous sodium chloride (50 mL), dried (Na₂SO₄), filtered, andconcentrated in vacuo. Silica gel column chromatography (EtOAc with 7%methanol) provided1-(4-chlorophenyl)-2-methyl-1H-imidazole-4-carbaldehyde (0.600 g, tansolid) in 69% yield. ¹H NMR (400 MHz, CDCl₃) δ 9.89 (s, 1H), 7.67 (s,1H), 7.53 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 2.40 (s, 3H). MSm/z 221.0 (M+H)⁺; Rt-0.47 min.

Intermediate 194:1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carbaldehyde

A mixture of 1H-pyrazole-3-carbaldehyde (0.700 g, 7.29 mmol),5-bromo-2-(trifluoromethyl)pyridine (2.31 g, 10.2 mmol, 1.4 equiv),cesium carbonate (4.75 g, 14.6 mmol, 2.0 equiv), copper(I) iodide (0.069g, 0.36 mmol, 0.05 equiv), and(1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.23 mL, 1.46 mmol, 0.2equiv) in DMF (9.5 mL) was heated in a sealed reaction vessel at 110° C.for 16 hours. The reaction was then cooled to room temperature andsaturated aqueous ammonium chloride (100 mL) was added. The mixture wasextracted with ethyl acetate (3×50 mL). The combined organic extractswere washed with saturated aqueous sodium chloride (50 mL), dried(Na₂SO₄), filtered, and concentrated in vacuo. Silica gel columnchromatography (EtOAc/heptane) provided1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carbaldehyde (0.470 g,brown solid) in 27% yield. ¹H NMR (400 MHz, CDCl₃) δ 10.13 (s, 1H), 9.18(d, J=2.1 Hz, 1H), 8.34 (dd, J=8.7, 2.0 Hz, 1H), 8.12 (m, 1H), 7.88 (d,J=8.5 Hz, 1H), 7.10 (d, J=1.8 Hz, 1H). MS m/z 241.9 (M+H)⁺; Rt-0.78 min.

Intermediate 195:(R,E)-N-((5-(4-chlorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide

A suspension of 5-(4-chlorophenyl)isoxazole-3-carbaldehyde (2.00 g, 9.63mmol), (R)-2-methylpropane-2-sulfinamide (1.28 g, 10.6 mmol, 1.1 equiv)and anhydrous copper(II) sulfate (2.31 g, 14.5 mmol, 1.5 equiv) in1,2-dichloroethane (19 mL) was heated at 55° C. for 2-18 hours. Thereaction was then cooled to room temperature and filtered through a padof celite, using 1,2-dichloroethane to wash through. The filtrate wasconcentrated in vacuo to give crude(R,E)-N-((5-(4-chlorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamideas a green solid, which was used without further purification. MS m/z311.0 (M+H)⁺; Rt-1.11 min.

The intermediates in Table 11a were prepared using a method similar tothat described for the preparation of Intermediate 195

TABLE 11a

Intermediate 196

Intermediate 197

Intermediate 198

Intermediate 199

Intermediate 200

Intermediate 201

Intermediate 202

Intermediate 203

Intermediate 204

Intermediate 205

Intermediate 206

Intermediate 207

Intermediate 208

Intermediate 209

Intermediate 210

Intermediate 211

Intermediate 212

Intermediate 213

Intermediate 214

TABLE 11b Chemical name and analytical data for each intermediate listedin Table 11a. Intermediate: Name Analytical data 196:(R,E)-N-((5-(4-chlorophenyl)isoxazol-3- MS m/zyl)methylene)-2-methylpropane-2-sulfinamide 311.0 (M + H)⁺; Rt-1.11 min197: (R,E)-N-((2-(4-chlorophenyl)thiazol-5- MS m/zyl)methylene)-2-methylpropane-2-sulfinamide 327.1 (M + H)⁺; Rt-1.13 min198: (R,E)-2-methyl-N-((5-phenylthiophen-2- MS m/zyl)methylene)propane-2-sulfinamide 292.0 (M + H)⁺; Rt-1.05 min 199:(R,E)-2-methyl-N-((5-phenylisoxazol-3- MS m/zyl)methylene)propane-2-sulfinamide 277.1 (M + H)⁺; Rt-1.02 min 200:(R,E)-N-((1-(4-chlorophenyl)-1H-pyrazol-4- MS m/zyl)methylene)-2-methylpropane-2-sulfinamide 310.1 (M + H)⁺; Rt-1.00 min201: (R,E)-N-((5-(4-fluorophenyl)isoxazol-3- MS m/zyl)methylene)-2-methylpropane-2-sulfinamide 295.1 (M + H)⁺; Rt-1.00 min202: (R,E)-N-((1-(4-fluorophenyl)-1H-pyrazol-4- MS m/zyl)methylene)-2-methylpropane-2-sulfinamide 294.1 (M + H)⁺; Rt-0.90 min203: (R,E)-2-methyl-N-((5-(pyridin-2-yl)thiophen-2- MS m/zyl)methylene)propane-2-sulfinamide 293.1 (M + H)⁺; Rt-0.85 min 204:(R,E)-2-methyl-N-((5-morpholinomethyl)isox- MS m/zazol-3-yl)methylene)propane-2-sulfinamide 300.1 (M + H)⁺; Rt-0.43 min205: (R,E)-2-methyl-N-((2-morpholinothiazol-5- MS m/zyl)methylene)propane-2-sulfinamide 302.1 (M + H)⁺; Rt-0.69 min 206:(R,E)-2-methyl-N-((2-(pyridin-2-yl)thiazol-5- MS m/zyl)methylene)propane-2-sulfinamide 294.2 (M + H)⁺; Rt-0.92 min 207:(R,E)-2-methyl-N-((2-(pyridin-3-yl)thiazol-5- MS m/zyl)methylene)propane-2-sulfinamide 294.1 (M + H)⁺; Rt-0.63 min 208:(R,E)-2-methyl-N-((2-(pyridin-4-yl)thiazol-5- MS m/zyl)methylene)propane-2-sulfinamide 294.1 (M + H)⁺; Rt-0.55 min 209:(R,E)-N-((2-(4-(difluoromethyl)phenyl)thiazol- MS m/z5-yl)methylene)-2-methylpropane-2-sulfinamide 342.9 (M + H)⁺; Rt-0.86min 210: (R,E)-2-methyl-N-((2-(6-methylpyridin-3- MS m/zyl)thiazol-5-yl)methylene)propane-2-sulfinamide 308.1 (M + H)⁺; Rt-0.58min 211: (R,E)-2-methyl-N-((2-(6-(trifluoromethyl)pyridin- MS m/z3-yl)thiazol-5-yl)methylene)propane-2-sulfinamide 362.1 (M + H)⁺;Rt-0.96 min 212: (R,E)-2-methyl-N-((2-(2-(trifluoromethyl)pyridin- MSm/z 4-yl)thiazol-5-yl)methylene)propane-2-sulfinamide 362.1 (M + H)⁺;Rt-0.97 min 213: (R,E)-2-methyl-N-((1-(6-(trifluoromethyl)pyridin- MSm/z 3-yl)-1H-pyrazol-3-yl)methylene)propane-2- 345.0 (M + H)⁺;sulfinamide Rt-0.95 min 214: (R,E)-N-((1-(4-chlorophenyl)-2-methyl-1H-MS m/z imidazol-4-yl)methylene)-2-methylpropane-2- 324.0 (M + H)⁺;sulfinamide Rt-0.62 min

Intermediate 215:(R)—N—((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide

A solution of methylmagnesium bromide (3.0 M in diethyl ether, 12.8 mL,38.4 mmol, 4 equiv) was added to a solution of(R,E)-N-((5-(4-chlorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide(2.98 g, 9.6 mmol) in DCM (96 mL) at 0° C. The solution became orange,then faded to yellow. The reaction was stirred at 0° C. for 30 min andthen carefully quenched with saturated aqueous ammonium chloride (100mL). The layers were separated and the aqueous layer was extracted withDCM (40 mL). The combined organic layers were washed with water (50 mL),saturated aqueous sodium chloride (50 mL), dried over Na₂SO₄, filteredand concentrated. Silica gel column chromatography (EtOAc/Heptane)provided(R)—N—((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide(1.0 g, white solid) in 32% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d,J=8.6 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 6.50 (s, 1H), 4.75 (m, 1H), 3.47(m, 1H), 1.70 (d, J=6.8 Hz, 3H), 1.25 (s, 9H). MS m/z 327.0 (M+H)⁺;Rt-0.94 min.

The intermediates in Table 12a were prepared using a method similar tothat described for the preparation of Intermediate 215.

TABLE 12a

Intermediate 216

Intermediate 217

Intermediate 218

Intermediate 219

Intermediate 220

Intermediate 221

Intermediate 222

Intermediate 223

Intermediate 224

Intermediate 225

Intermediate 226

Intermediate 227

Intermediate 228

Intermediate 229

Intermediate 230

Intermediate 231

Intermediate 232

Intermediate 233

Intermediate 234

Intermediate 235

TABLE 12b Chemical name, NMR chemical shifts and LCMS signal for eachintermediate listed in Table 12a. Intermediate: Name ¹H NMR (400 MHz,CDCl₃) δ ppm LCMS 216: (R)-N-((S)-1-(5-(4- 7.71 (d, J = 8.6 Hz, 2H),7.45 MS m/z chlorophenyl)isoxazol-3-yl)ethyl)-2- (d, J = 8.6 Hz, 2H),6.50 (s, 1H), 327.0 (M + H)⁺; methylpropane-2-sulfinamide 4.75 (m, 1H),3.47 (m, 1H), 1.70 Rt-0.94 min (d, J = 6.8 Hz, 3H), 1.25 (s, 9H). 217:(R)-N-((S)-1-(2-(4-chlorophenyl)thiazol- CD₃OD: 7.88 (d, J = 8.7 Hz, MSm/z 5-yl)ethyl)-2-methylpropane-2-sulfinamide 2H), 7.73 (d, J = 1.0 Hz,1H), 343.1 (M + H)⁺; 7.47 (d, J = 8.7 Hz, 2H), 4.83 Rt-0.97 min (m, 1H),1.71 (d, J = 6.7 Hz, 3H), 1.25 (s, 9H) 218: (R)-2-methyl-N-((S)-1-(5-7.58 (d, J = 7.4 Hz, 2H), 7.37 MS m/zphenylthiophen-2-yl)ethyl)propane-2- (m, 2H), 7.27 (m, 1H), 7.16 (d,308.1 (M + H)⁺; sulfinamide J = 3.7 Hz, 1H), 6.95 (d, J = 3.7 Rt-0.95min Hz, 1H), 4.84 (m, 1H), 3.42 (m, 1H), 1.70 (d, J = 6.6 Hz, 3H), 1.26(s, 9H) 219: (R)-2-methyl-N-((S)-1-(5- MS m/zphenylisoxazol-3-yl)ethyl)propane-2- 293.2 (M + H)⁺; sulfinamide Rt-0.85min 220: (R)-N-((S)-1-(1-(4-chlorophenyl)-1H- 7.84 (s, 1H), 7.63 (s,1H), 7.61 MS m/z pyrazol-4-yl)ethyl)-2-methylpropane-2- (d, J = 8.7 Hz,2H), 7.42 (d, J = 326.1 (M + H)⁺; sulfinamide 8.7 Hz, 2H), 4.64 (m, 1H),3.31 Rt-0.89 min (m, 1H), 1.62 (d, J = 6.7 Hz, 3H), 1.24 (s, 9H) 221:(R)-N-((S)-1-(5-(4- 7.77 (dd, J = 8.9, 5.2 Hz, 2H), MS m/zfluorophenyl)isoxazol-3-yl)ethyl)-2- 7.16 (t, J = 8.7 Hz, 2H), 6.46 (s,311.1 (M + H)⁺; methylpropane-2-sulfinamide 1H), 4.77 (m, 1H), 3.47 (d,J = Rt-0.85 min 5.7 Hz, 1H), 1.70 (d, J = 6.8 Hz, 3H), 1.25 (s, 9H) 222:(R)-N-((S)-1-(1-(4-fluorophenyl)-1H- 7.80 (s, 1H), 7.63 (m, 3H), 7.14 MSm/z pyrazol-4-yl)ethyl)-2-methylpropane-2- (t, J = 8.5 Hz, 2H), 4.63 (m,1H), 310.1 (M + H)⁺; sulfinamide 3.31 (d, J = 5.0 Hz, 1H), 1.62 Rt-0.79min (d, J = 6.7 Hz, 3H), 1.24 (s, 9H) 223:(R)-2-methyl-N-((S)-1-(5-(pyridin-2- 8.53-8.59 (m, 1 H), 7.60-7.73 MSm/z yl)thiophen-2-yl)ethyl)propane-2-sulfinamide (m, 2 H), 7.43 (d, J =3.7 Hz, 1 309.1 (M + H)⁺; H), 7.15 (ddd, J = 7.1, 5.0, 1.2 Rt-0.58 minHz, 1 H), 6.99 (d, J = 3.8 Hz, 1 H), 4.84 (quin, J = 6.3 Hz, 1 H), 3.43(d, J = 5.5 Hz, 1 H), 1.70 (d, J = 6.6 Hz, 3 H), 1.26 (s, 9 H) 224:(R)-2-methyl-N-((S)-1-(5- MS m/z (morpholinomethyl)isoxazol-3- 316.1(M + H)⁺; yl)ethyl)propane-2-sulfinamide Rt-0.38 min 225:(R)-2-methyl-N-((S)-1-(2- 7.06 (s, 1H), 4.69 (quin, J = 6.1morpholinothiazol-5-yl)ethyl)propane-2- Hz, 1H), 3.81 (m, 4H), 3.44 (m,sulfinamide 4H), 3.32 (d, J = 4.9 Hz, 1H), 1.60 (d, J = 6.6 Hz, 3H),1.22 (s, 9H) 226: (R)-2-methyl-N-((S)-1-(2-(pyridin-2- 8.60 (m, 1H),8.15 (m, 1H), 7.80 MS m/z yl)thiazol-5-yl)ethyl)propane-2-sulfinamide(m, 2H), 7.33 (m, 1H), 4.93 (m, 310.0 (M + H)⁺; 1H), 1.71 (d, J = 6.6Hz, 3H), Rt-0.69 min 1.25 (s, 9H) 227:(R)-2-methyl-N-((S)-1-(2-(pyridin-3- 9.11 (m, 1H), 8.65 (m, 1H), 8.23 MSm/z yl)thiazol-5-yl)ethyl)propane-2-sulfinamide (m, 1H), 7.75 (m, 1H),7.38 (m, 310.0 (M + H)⁺; 1H), 4.90 (m, 1H), 3.50 (m, 1H), Rt-0.50 min1.71 (d, J = 6.6 Hz, 3H), 1.24 (s, 9H) 228:(R)-2-methyl-N-((S)-1-(2-(pyridin-4- 8.70 (m, 2H), 7.79 (m, 3H), 4.94 MSm/z yl)thiazol-5-yl)ethyl)propane-2-sulfinamide (m, 1H), 1.72 (d, J =6.6 Hz, 3H) 310.2 (M + H)⁺; Rt-0.46 min 229: (R)-N-((S)-1-(2-(4- 8.01(d, J = 8.0 Hz, 2H), 7.74 MS m/z(difluoromethyl)phenyl)thiazol-5-yl)ethyl)-2- (s, 1H), 7.59 (d, J = 8.0Hz, 2H), 359.1 (M + H)⁺; methylpropane-2-sulfinamide 6.69 (t, J = 56 Hz,1H), 4.91 (m, Rt-0.89 min 1H), 3.45 (d, J = 4.7 Hz, 1H), 1.72 (d, J =6.6 Hz, 3H), 1.25 (s, 9H) 230: (R)-2-methyl-N-((S)-1-(2-(6- 9.01 (d, J =2.2 Hz, 1H), 8.10 MS m/z methylpyridin-3-yl)thiazol-5- (dd, J = 8.1, 2.3Hz, 1H), 7.73 324.1 (M + H)⁺; yl)ethyl)propane-2-sulfinamide (s, 1H),7.24 (d, J = 8.2 Hz, 1H), Rt-0.49 min 4.91 (m, 1H), 3.46 (d, J = 4.8 Hz,1H), 2.62 (s, 3H), 1.72 (d, J = 6.6 Hz, 3H), 1.25 (s, 9H) 231:(R)-2-methyl-N-((S)-1-(2-(6- 9.23 (s, 1H), 8.40 (d, J = 8.3 MS m/z(trifluoromethyl)pyridin-3-yl)thiazol-5- Hz, 1H), 7.82 (s, 1H), 7.78 (d,378.1 (M + H)⁺; yl)ethyl)propane-2-sulfinamide J = 8.3 Hz, 1H), 4.95 (m,1H), Rt-0.84 min 3.49 (d, J = 4.1 Hz, 1H), 1.74 (d, J = 6.6 Hz, 3H),1.26 (s, 9H) 232: (R)-2-methyl-N-((S)-1-(2-(2- 8.82 (d, J = 5.0 Hz, 1H),8.19 MS m/z (trifluoromethyl)pyridin-4-yl)thiazol-5- (s, 1H), 7.97 (dd,J = 5.0, 1.6 378.1 (M + H)⁺; yl)ethyl)propane-2-sulfinamide Hz, 1H),7.85 (s, 1H), 4.95 (m, Rt-0.85 min 1H), 3.49 (d, J = 4.5 Hz, 1H), 1.74(d, J = 6.6 Hz, 3H), 1.26 (s, 9H) 233: (R)-2-methyl-N-((R)-1-(5- MS m/z(morpholinomethyl)isoxazol-3- 316.2 (M + H)⁺;yl)ethyl)propane-2-sulfinamide Rt-0.43 min 234:(R)-2-methyl-N-((S)-1-(1-(6- 9.06 (d, J = 2.3 Hz, 1H), 8.22 MS m/z(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3- (dd, J = 8.6, 1.9 Hz, 1H),7.98 361.1 (M + H)⁺; yl)ethyl)propane-2-sulfinamide (dd, J = 2.6, 0.9Hz, 1H), 7.78 Rt-0.85 min (d, J = 8.6 Hz, 1H), 6.51 (dd, J = 2.5, 0.9Hz, 1H), 4.76 (m, 1H), 3.48 (d, J = 4.1 Hz, 1H), 1.68 (d, J = 6.8 Hz,3H), 1.24 (s, 9H) 235: (R)-N-((S)-1-(1-(4-chlorophenyl)-2- 7.45 (d, J =8.6 Hz, 2H), 7.24 MS m/z methyl-1H-imidazol-4-yl)ethyl)-2- (d, J = 8.6Hz, 2H), 6.87 (s, 1H), 340.1 (M + H)⁺; methylpropane-2-sulfinamide 4.54(m, 1H), 3.48 (d, J = 5.8 Rt-0.64 min Hz, 1H), 2.33 (s, 3H), 1.65 (d, J= 6.8 Hz, 3H), 1.22 (s, 9H)

Intermediate 236:(R)—N—((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

Step 1

To an oven dried round bottom flask with stir bar was added4-bromo-2-fluorobenzaldehyde (5 g, 24.6 mmol),(R)-2-methylpropane-2-sulfinamide (3.28 g, 27.1 mmol) and DCE (49 mL).To this mixture was then added copper (II) sulfate (5.90 g, 36.9 mmol).Reaction mixture was heated in a preheated oil bath to 55° C. for 18hours. Reaction mixture was filtered through a pad celite, washing thesolids with CH₂Cl₂. The filtrate was concentrated to afford a viscousyellow oil of(R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide(7.73 g, 25.2 mmol, 103% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.27 (s, 9H)7.31-7.42 (m, 2H) 7.87 (t, J=7.87 Hz, 1H) 8.83 (s, 1H). LCMS m/z 307.9(M+H)⁺, Rt 1.01 min.

Step 2

To a solution of(R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide(7.73 g, 25.2 mmol) in CH₂Cl₂ (252 mL), cooled to 0° C. (water/ice bath)under nitrogen, was added 3M methyl magnesium bromide (33.7 mL, 101mmol) in Et₂O. Reaction mixture allowed to stir for 30 min at 0° C.,then gradually allowed to warm to room temperature and stirred for 1hour at room temperature. Reaction mixture was cooled to 0° C. thenquenched with the slow addition of a saturated solution of NH₄Cl.Aqueous mixture extracted with EtOAc. Organic phases combined, washedwith water, brine, dried (Na₂SO₄), filtered and concentrated onto silicagel. Silica gel column chromatography (EtOAc/Heptane 40 to 100%)provided(R)—N—((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(4.93 g, 15.3 mmol, 60% yield) as a white crystalline solid. ¹H NMR (400MHz, CDCl₃) δ 1.20 (s, 9H) 1.56 (d, J=6.70 Hz, 3H) 3.34 (br. s., 1H)4.77-4.87 (m, 1H) 7.19-7.31 (m, 3H). LCMS m/z 324.0 (M+H)⁺, Rt 0.90 min.

Step 3

To a microwave vial with stir bar was added(R)—N—((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2- (1 g,3.10 mmol), isopropenyl boronic acid pinacol ester (1.51 ml, 8.07 mmol),DME (8 ml), sodium carbonate (7.76 ml, 15.5 mmol) (2.0 M aq) andPdCl₂(dppf). CH₂Cl₂ adduct (0.127 g, 0.155 mmol). Vessel was capped andheated by microwave irradiation for 20 min at 100° C. Reaction mixturewas diluted with a saturated solution of NH₄Cl. The aqueous mixture wasextracted with EtOAc. Organic phases combined, washed with water, brine,dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gelcolumn chromatography (EtOAc/Heptane 50 to 100%) provided(R)—N—((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(830 mg, 2.93 mmol, 94% yield) as a pale brown crystalline. ¹H NMR (400MHz, DMSO) δ 1.08-1.11 (m, 9H) 1.47 (d, J=6.80 Hz, 3H) 2.09 (d, J=0.54Hz, 3H) 4.61-4.71 (m, 1H) 5.14 (t, J=1.32 Hz, 1H) 5.43 (d, J=5.58 Hz,1H) 5.49 (s, 1H) 7.24-7.30 (m, 1H) 7.31-7.36 (m, 1H) 7.41-7.47 (m, 1H).LCMS m/z 284.0 (M+H)⁺, Rt 0.93 min.

Step 4

To a round bottom flask containing(R)—N—((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-(0.37 g, 1.31 mmol) in DCE (13 mL) at 0° C. was added under argondiethylzinc (1.0M in hexanes) (13.1 mL, 13.1 mmol) followed by thedropwise addition of chloroiodomethane (0.95 mL, 13.1 mmol). Reactionmixture allowed to warm to room temperature and stirred for 1 hour.Reaction mixture was cooled to 0° C. whereupon a second addition ofdiethylzinc (1.0M in hexanes) (13.1 mL, 13.1 mmol) took place followedby the addition of chloroiodomethane (0.95 mL, 13.1 mmol). Reactionmixture allowed to warm to room temperature and stirred 18 hours underargon. Reaction mixture was cooled to 0° C. in a ice bath and to thecold reaction mixture was slowly added a saturated solution of NH₄Cl.The aqueous mixture was extracted with EtOAc. Organic phases combined,washed with water, brine, dried (Na₂SO₄), filtered and concentrated ontosilica gel. Silica gel column chromatography (EtOAc/Heptane 20 to 100%)provided a white crystalline of(R)—N—((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(89 mg, 0.299 mmol, 22.92% yield). ¹H NMR (400 MHz, CDCl₃) δ 0.75-0.79(m, 2H) 0.85-0.90 (m, 2H) 1.20 (s, 9H) 1.55 (s, 3H) 1.57 (d, J=6.80 Hz,1H) 3.34 (d, J=5.23 Hz, 1H) 4.75-4.85 (m, 1H) 6.90 (dd, J=12.30, 1.74Hz, 1H) 6.97 (dd, J=8.05, 1.78 Hz, 1H) 7.22 (t, J=7.97 Hz, 1H). LCMS m/z298.1 (M+H)⁺, Rt 1.01 min.

Intermediate 237:(R)—N—((S)-1-(4-(1-ethoxycyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

Step 1

To a microwave vial with stir bar was added(R)—N—((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(500 mg, 1.55 mmol) followed by the addition oftributyl(1-ethoxyvinyl)stannane (1.12 g, 3.10 mmol), triethylamine (0.65ml, 4.65 mmol) and PdCl₂(dppf). CH₂Cl₂ adduct (63 mg, 0.078 mmol). Tothe solids was added toluene (10 ml). Vial capped and heated in apreheated sand bath at 100° C. for 1 hour. Reaction mixture was loadedonto silica gel column. Silica gel column chromatography (MeOH/CH₂Cl₂ 0to 10% with 1% NH₄OH buffer) provided(R)—N—((S)-1-(4-(1-ethoxyvinyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(498 mg, 1.59 mmol, 102% yield) as a brown viscous oil whichcrystallizes upon standing. ¹H NMR (400 MHz, CDCl₃) δ 1.20 (s, 9H) 1.43(t, J=6.97 Hz, 3H) 1.58 (d, J=6.75 Hz, 3H) 3.35 (d, J=4.74 Hz, 1H) 3.92(q, J=6.96 Hz, 2H) 4.23 (d, J=2.79 Hz, 1H) 4.65 (d, J=2.79 Hz, 1H)4.79-4.89 (m, 1H) 7.16-7.20 (m, 1H) 7.29-7.34 (m, 1H) 7.39 (dd, J=8.07,1.66 Hz, 1H).

Step 2

To a round bottom flask containing(R)—N—((S)-1-(4-(1-ethoxyvinyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(0.49 g, 1.56 mmol) and chloroiodomethane (1.14 mL, 15.6 mmol) intoluene (15 mL) at 0° C. under argon was added diethylzinc (1.0M inhexanes) (15.6 mL, 15.6 mmol). Reaction mixture allowed to warm to roomtemperature and stirred for 1 hour. Reaction mixture was cooled to 0° C.in an ice bath and to the cold reaction mixture was slowly added asaturated solution of NH₄Cl. The aqueous mixture was extracted withEtOAc. Organic phases combined, washed with water, brine, dried(Na₂SO₄), filtered and concentrated onto silica gel. Silica gel columnchromatography (MeOH/CH₂Cl₂ 0 to 10%) provided(R)—N—((S)-1-(4-(1-ethoxycyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(145 mg, 0.44 mmol, 28% yield) as a viscous brown oil. ¹H NMR (300 MHz,CDCl₃) δ 0.93-0.99 (m, 2H) 1.14-1.20 (m, 3H) 1.21 (s, 9H) 1.22-1.27 (m,2H) 1.57-1.61 (m, 4H) 3.35 (d, J=4.98 Hz, 1H) 3.45 (q, J=7.07 Hz, 2H)4.77-4.87 (m, 1H) 6.98 (dd, J=7.58, 1.43 Hz, 3H) 7.00-7.03 (m, 4H)7.28-7.32 (m, 1H). LCMS m/z 328.1 (M+H)⁺, Rt 0.95 min.

Intermediate 238:(R)—N—((S)-1-(4-(1-cyanocyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

Step 1

To a microwave vial with a stir bar was added(R)—N—((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(300 mg, 0.93 mmol), 4-isoxazoleboronic acid pinacol ester (218 mg, 1.12mmol), PdCl₂(dppf).CH₂Cl₂ adduct (76 mg, 0.09 mmol), potassium fluoride(2.7 mL, 1.0 M in water, 2.79 mmol) and finally DMSO (9 mL). Thereaction mixture was degassed with bubbling nitrogen (3 min) and thevial capped and heated in a preheated oil bath at 130° C. for 18 hours.The reaction mixture was diluted with a saturated solution of NH₄Cl andextracted with EtOAc. Organic phases combined, washed with water, brine,dried (Na₂SO₄), filtered and concentrated onto silica gel. Silica gelcolumn chromatography (EtOAc/Heptanes 40 to 100%) provided(R)—N—((S)-1-(4-(cyanomethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(136 mg, 0.48 mmol, 52% yield) as a viscous brown oil. ¹H NMR (400 MHz,CDCl₃) δ 1.19 (s, 9H) 1.57 (d, J=6.80 Hz, 3H) 3.39 (d, J=4.35 Hz, 1H)3.74 (s, 2H) 4.81-4.88 (m, 1H) 7.04 (d, J=10.66 Hz, 1H) 7.11 (d, J=7.97Hz, 1H) 7.38 (t, J=7.73 Hz, 1H). LCMS m/z 283.0 (M+H)⁺, Rt 0.72 min.

Step 2

To a scintillation vial containing(R)—N—((S)-1-(4-(cyanomethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-(86 mg, 0.31 mmol) and a stir bar was added toluene (2 mL). To thismixture was then added tetrabutylammonium bromide (19 mg, 0.06 mmol)followed by the addition of NaOH (1.52 ml, 1.0 M (aq), 1.52 mmol) and1,2-dibromoethane (0.11 ml, 1.22 mmol). Vial capped and reaction mixturewas stirred vigorously at room temperature for 18 hours. Whereupon,1,2-dibromoethane (0.11 ml, 1.22 mmol) and tetrabutylammonium bromide(19 mg, 0.06 mmol) were added and reaction mixture allowed to stir anadditional 18 hours. A third addition of 1,2-dibromoethane (0.11 ml,1.22 mmol) was added and the reaction mixture heated to 50° C. for anadditional 18 hours in a preheated aluminum tray. The reaction mixturewas quenched with a saturated solution of NH₄Cl and the aqueous mixtureextracted with EtOAc. Organics combined and washed twice with water,brine, dried (Na₂SO₄), filtered and concentrated. Crude material waspassed through a small plug of silica gel using 10% MeOH:90% DCM toelute product. The solution was concentrated to afford a viscous orangeoil of(R)—N—((S)-1-(4-(1-cyanocyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(23 mg, 0.08 mmol, 24% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.20 (s, 9H)1.38-1.44 (m, 2H) 1.56 (d, J=6.75 Hz, 3H) 1.73-1.79 (m, 2H) 3.37 (d,J=4.45 Hz, 1H) 4.78-4.88 (m, 1H) 6.94 (dd, J=11.35, 1.91 Hz, 1H) 7.09(dd, J=8.07, 1.91 Hz, 1H) 7.34 (t, J=7.90 Hz, 1H). LCMS m/z 309.2(M+H)⁺, Rt 0.83 min.

Intermediate 239:(R)—N—((S)-1-(2-fluoro-4-isopropylphenyl)ethyl)-2-methylpropane-2-sulfinamide

To a round bottom flask containing(R)—N—((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(204 mg, 0.72 mmol) and a stir bar was added MeOH (7.2 mL). To thissolution was added palladium on carbon (77 mg, 10%, 0.07 mmol) in MeOH(1 mL). A hydrogen atmosphere was inserted and the resulting reactionmixture stirred at room temperature for 18 hours, at which time morepalladium on carbon was added (300 mg) in MeOH (5 mL). A hydrogenatmosphere was inserted again and the reaction mixture allowed to stiran additional 18 hours at room temperature. The reaction mixture wasfiltered through a syringe filter and concentrated to afford a lightbrown viscous oil of(R)—N—((S)-1-(2-fluoro-4-isopropylphenyl)ethyl)-2-methylpropane-2-sulfinamide(149 mg, 0.52 mmol, 73% yield) which crystallizes upon standing. ¹H NMR(400 MHz, CDCl₃) δ 1.20 (s, 9H) 1.24 (d, J=5.87 Hz, 6H) 1.58 (d, J=6.70Hz, 3H) 2.89 (dt, J=13.79, 6.90 Hz, 1H) 3.35 (d, J=5.04 Hz, 1H)4.76-4.85 (m, 1H) 6.90 (dd, J=12.03, 1.52 Hz, 1H) 6.98 (dd, J=7.90, 1.54Hz, 1H) 7.24 (t, J=7.97 Hz, 1H). LCMS m/z 286.3 (M+H)⁺, Rt 1.01 min.

Intermediate 240:(R)—N—((S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

To a two microwave vials with stir bars were added(R)—N—((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(1.5 g, 4.65 mmol), 1-methyl-4-1H-pyrazoleboronic acid pinacol ester(2.91 g, 13.9 mmol), DME (20 mL), sodium carbonate (11.6 mL, 23.3 mmol,2.0 M aq) and PdCl₂(dppf).CH₂Cl₂ adduct (190 mg, 0.23 mmol) dividedbetween the two vials. The vials were capped and heated by microwaveirradiation for 20 min at 100° C. respectively. The reaction mixturescombined, diluted with a saturated solution of NH₄Cl and EtOAc. Thephases were partitioned and the aqueous phase extracted with EtOAc.Organic phases combined, washed with water, brine, dried (Na₂SO₄),filtered and concentrated onto silica gel. Silica gel columnchromatography (EtOAc/Heptane 40 to 100%) provided a orange crystallineof(R)—N—((S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(1.07 g, 3.31 mmol, 71% yield. ¹H NMR (400 MHz, CDCL₃) δ ppm 1.21 (s,9H) 1.60 (d, J=6.80 Hz, 3H) 3.36 (d, J=4.25 Hz, 1H) 3.96 (s, 3H)4.79-4.91 (m, 1H) 7.13 (dd, J=11.69, 1.61 Hz, 1H) 7.23 (dd, J=8.00, 1.64Hz, 1H) 7.30-7.37 (m, 1H) 7.60 (s, 1H) 7.74 (s, 1H). LCMS m/z 324.0(M+H)⁺, Rt 0.74 min.

The Intermediates in Table 13a were prepared by a method similar to theone described for the preparation of Intermediate 240.

TABLE 13a

Intermediate 241

Intermediate 242

TABLE 13b Chemical name, NMR chemical shifts and LCMS signal for eachintermediate listed in Table 13. Intermediate: Name ¹H NMR (400 MHz) δppm LCMS 241: (R)-2-methyl-N-((S)-1-(4-(1- MS m/z methyl-1H-pyrazol-4-306.0 (M + H)⁺, yl)phenyl)ethyl)propane-2- Rt 0.71 min. sulfinamide 242:(R)-N-((S)-1-(2-fluoro-4- (DMSO) 1.10 (s, 9 H) 1.47 (d, J = 6.75 Hz, 3MS m/z (1H-pyrazol-4-yl)phenyl)ethyl)-2- H) 4.60-4.70 (m, 1 H) 5.41 (d,J = 5.48 Hz, 310.0 (M + H)⁺, methylpropane-2-sulfinamide 1 H) 7.38-7.44(m, 3 H) 7.96 (br. s., 1 H) Rt 0.67 min. 8.23 (br. s., 1 H) 12.97 (br.s., 1 H)

Intermediate 243:(R)—N—((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

Step 1

To a oven dried round bottom flask with stir bar was added2-fluoro-4-(trifluoromethyl) benzaldehyde (5 g, 26.0 mmol),(R)-2-methylpropane-2-sulfinamide (3.47 g, 28.6 mmol) and DCE (52 mL).To this mixture was then added copper (II) sulfate (6.23 g, 39.0 mmol).The reaction mixture was heated in a preheated oil bath at 55° C. for 18hours. The reaction mixture was filtered through a pad celite, washingthe solids with DCE. The filtrate was concentrated to afford a viscousgreen oil of (R,E)-N-(2-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (7.3 g, 24.7 mmol, 95% yield). Material was takenonto next step without further purification. ¹H NMR (400 MHz, CDCl₃) δppm 1.29 (s, 9H) 7.44 (d, J=10.08 Hz, 1H) 7.51 (d, J=8.27 Hz, 1H) 8.13(t, J=7.46 Hz, 1H) 8.92 (s, 1H). LCMS m/z 296.0 (M+H)⁺, Rt 1.02 min.

Step 2

To a solution of (R,E)-N-(2-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (7.3 g, 24.7 mmol) in CH₂Cl₂(247 mL) cooled to 0° C. (water/ice bath) under nitrogen, was added 3Mmethyl magnesium bromide (33 mL, 99 mmol) in Et₂O. Reaction mixtureallowed to stir for 30 min at 0° C., then gradually allowed to warm toroom temperature and stirred for 1 hour at room temperature. Reactionmixture was cooled to 0° C. then quenched with the slow addition of asaturated solution of NH₄Cl. Aqueous mixture extracted with EtOAc.Organic phases combined, washed with water, brine, dried (Na₂SO₄),filtered and concentrated onto silica gel. Silica gel columnchromatography (EtOAc/Heptane 40 to 100%) provided(R)—N—((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(4.68 g, 15.0 mmol, 61% yield) as a white crystalline solid. ¹H NMR (400MHz, CDCL₃) δ 1.22 (s, 9H) 1.60 (d, J=6.80 Hz, 3H) 3.38 (d, J=4.01 Hz,1H) 4.87-4.97 (m, 1H) 7.33 (d, J=10.32 Hz, 1H) 7.39-7.45 (m, 1H)7.49-7.55 (m, 1H). LCMS m/z 312.0 (M+H)⁺, Rt 0.92 min.

Intermediate 244: (S)-tert-butyl1-(3-chloro-4-(cyclopentylcarbamoyl)phenyl)ethyl Carbamate

Step 1

To a round bottom flask with stir bar was added4-((S)-1aminoethyl-2-chlorobenzoic acid HCl salt (1.05 g, 4.45 mmol)followed by the addition of THF (40 mL). To this solution was added DIEA(1.86 ml, 10.7 mmol). The reaction mixture becomes cloudy white followedby the addition of di-tert-butyl dicarbonate (1.07 g, 4.89 mmol).Resulting reaction mixture allowed to stir for 18 hours at roomtemperature. At which time the reaction mixture was then heated to 60°C. for 2 hours in a oil bath. Di-tert-butyl dicarbonate (1.07 g, 4.89mmol) and NMP (20 ml) were then added and the resulting reaction mixtureallowed to stir for 2 hours at 60° C. Volatiles were removed. Theresulting oil was diluted with a saturated solution of NH₄Cl and theaqueous mixture extracted with EtOAc. The organic phases combined,washed twice with water, brine, dried (Na₂SO₄), filtered andconcentrated to a viscous yellow oil of(S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-chlorobenzoic acid (2.32 g,6.19 mmol, 139% yield) which contains some excess di-tert-butyldicarbonate and NMP. LCMS m/z 284.9 (M+H)⁺(carboxylic acidfragment+CH₃CN adduct), Rt 0.75 min.

Step 2

To a round bottom flask with stir bar was added(S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-chlorobenzoic acid (450 mg,1.20 mmol), cyclopentylamine (355 μL, 3.60 mmol), EDC HCl (460 mg, 2.40mmol), 1-hydroxy-7-aza-benzotriazole (229 mg, 1.68 mmol) and DMF (6 mL).To this mixture was then added DIEA (629 μL, 3.60 mmol). Reactionmixture was allowed to stir at room temperature for 18 hours. Thereaction mixture was diluted with water and extracted with EtOAc. Theorganic phases were combined, washed with twice with water, brine, dried(Na₂SO₄), filtered and concentrated to a brown crystalline of(S)-tert-butyl 1-(3-chloro-4-(cyclopentylcarbamoyl)phenyl)ethylcarbamate (476 mg, 1.17 mmol, 97% yield). LCMS m/z 367.0(M+H)⁺, Rt 0.90 min.

Intermediate 245:(R)—N—((S)-1-(2,5-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

Step 1

To a round bottom flask with stir bar was added4-bromo-2,5-difluorobenzaldehyde (5.3 g, 24.0 mmol),(R)-2-methylpropane-2-sulfinamide (3.2 g, 26.4 mmol) and DCE (80 mL). Tothis mixture was then added copper (II) sulfate (5.74 g, 36.0 mmol). Thereaction mixture was heated in a preheated oil bath at 60° C. for 18hours. The reaction mixture was filtered through a pad celite, washingthe solids with DCE. The filtrate was concentrated to afford a viscousgreen oil of(R,E)-N-(4-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide(7.2 g, 22.2 mmol, 93% yield). Material was taken onto next step withoutfurther purification. LCMS m/z 326.0 (M+H)⁺, Rt 1.04 min.

Step 2

To a solution of(R,E)-N-(4-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide(7.2 g, 22.2 mmol in CH₂CO₂ (200 mL) cooled to 0° C. (water/ice bath)under nitrogen, was added 3M methyl magnesium bromide (29.6 mL, 89 mmol)in Et₂O. Reaction mixture allowed to stir for 5 hours at 0° C. thenquenched with the slow addition of a saturated solution of NH₄Cl.Aqueous mixture adjusted to pH 8 with HCl (1 N) and extracted with DCM.Organic phases combined, washed with water, brine, dried (Na₂SO₄),filtered and concentrated onto silica gel. Silica gel columnchromatography (EtOAc/Heptane 30 to 100%) provided(R)—N—((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(6.86 g, 20.2 mmol, 91% yield) LCMS m/z 342.1 (M+H)⁺, Rt 0.96 min.

Step 3

To two microwave vials with stir bars were added(R)—N—((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (500 mg, 1.47 mmol),1-Methyl-4-1H-pyrazoleboronic acid, pinacol ester (917 mg, 4.41 mmol),DME (6 ml), Na₂CO₃ (3.67 ml, 7.35 mmol) (2.0 M aq) andPdCl₂(dppf).CH₂Cl₂ adduct (60.0 mg, 0.07 mmol) divided evenly betweenthe two vessels. Vessels were capped and heated by microwave irradiationfor 20 min at 100° C. Reaction mixtures were combined, diluted with asaturated solution of NH₄Cl and EtOAc. Phases partitioned. Aqueous phaseextracted with EtOAc and organic phases combined, washed with water,brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silicagel column chromatography (EtOAc/Heptane 60 to 100%) provided(R)—N—((S)-1-(2,5-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(370 mg, 1.08 mmol, 73.7% yield). ¹H NMR (400 MHz, CDCL₃) δ ppm 1.23 (s,9H) 1.57-1.60 (m, 3H) 3.33 (d, J=4.06 Hz, 1H) 3.97 (s, 3H) 4.79-4.88 (m,1H) 7.10 (dd, J=11.20, 6.06 Hz, 1H) 7.20 (dd, J=10.78, 6.19 Hz, 1H) 7.76(d, J=2.20 Hz, 1H) 7.82 (s, 1H). LCMS m/z 342.1 (M+H)⁺, Rt 0.77 min.

Intermediate 246:(S)—N—((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide

Step 1

To a mixture of 1H-imidazole-4-carbaldehyde (3.71 g, 38.6 mmol),1-chloro-4-iodobenzene (13.81 g, 57.9 mmol),(1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (1.10 g, 7.72 mmol),copper(I) iodide (0.368 g, 1.93 mmol) and cesium carbonate (25.2 g, 77mmol) was added DMF (50 mL). The reaction was sealed and heated to 110°C. for 18 hours. The reaction mixture was then cooled to roomtemperature and diluted with a saturated solution of NH₄Cl. A brownsolid develops. Solid was collected, washed with water and air dried.Solid material was then dissolved in 10% MeOH:90% DCM solution and dried(Na₂SO₄), filtered and concentrated to afford a dark brown solid1-(4-chlorophenyl)-1H-imidazole-4-carbaldehyde (8.55 g, 41.4 mmol, 107%yield). Material as used without further purification. LCMS m/z 207.1(M+H)⁺, Rt 0.58 min.

Step 2

To a suspension of (S)-(−)tert-Butanesulfinamide (2.35 g, 19.4 mmol) and1-(4-chlorophenyl)-1H-imidazole-4-carbaldehyde (4 g, 19.4 mmol) in DCE(39 mL) was added CuSO₄ (4.63 g, 29.0 mmol). The reaction mixture washeated at 60° C. for 18 hours in a oil bath. A dark brown suspensionresulted. The reaction mixture was then cooled to room temperature,filtered through a pad of celite, rinsed with DCM. The solution was thenconcentrated onto silica gel. Silica gel column chromatography(EtOAc/Heptane 0 to 100%) provided(S,E)-N-((1-(4-chlorophenyl)-1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide(1.69 g, 5.45 mmol, 28.2% yield) as a light brown solid. LCMS m/z 310.0(M+H)⁺, Rt 0.75 min.

Step 3

To a solution of(S,E)-N-((1-(4-chlorophenyl)-1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide(1.69 g, 5.45 mmol) in DCM (27 mL), cooled to −40° C. (acetone/dry ice)under N₂, was added 3M MeMgBr (7.27 ml, 21.8 mmol) in diethyl ether.Reaction mixture allowed to stir for 1 hr at −40° C. Reaction mixturewas quenched with the slow addition of a saturated solution of NH₄Cl anddiluted with EtOAc. Phases partitioned, aqueous phase extracted withEtOAc and the organic layers combined washed with water, brine, dried(Na₂SO₄), filtered and concentrated onto silica gel. Silica gel columnchromatography (EtOAc/MeOH:EtOAc 0 to 5%) provided(S)—N—((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide(1.11 g, 3.41 mmol, 62% yield). ¹H NMR (400 MHz, CDCL₃) δ 1.25 (s, 9H)1.58 (d, J=6.65 Hz, 3H) 3.80 (d, J=5.48 Hz, 1H) 4.59 (quin, J=6.36 Hz,1H) 7.26 (s, 1H) 7.33 (d, J=8.61 Hz, 2H) 7.41-7.47 (m, 2H) 7.76 (d,J=1.17 Hz, 1H). LCMS m/z 326.1 (M+H)⁺, Rt 0.59 min.

Intermediate 247: (S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethanamine

A solution of hydrochloric acid (4.0 M in 1,4-dioxane, 2.1 mL, 8.2 mmol,2 equiv) was added to a solution of(R)—N—((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide(1.34 g, 4.1 mmol) in 1,4-dioxane at room temperature. A precipitateformed. The suspension was stirred for 1 hour and then concentrated invacuo to give the hydrochloride salt of(S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethanamine (1.1 g, light yellowsolid), which was used without purification. ¹H NMR (400 MHz, CD₃OD) δ7.87 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 6.98 (s, 1H), 4.72 (q,J=6.9 Hz, 1H), 1.72 (d, J=7.0 Hz, 3H). MS m/z 223.1 (M+H)⁺; Rt-0.59 min.

The intermediates in Table 14a were prepared using a method similar tothat described for the preparation of Intermediate 247.

TABLE 14a

Intermediate 248

Intermediate 249

Intermediate 250

Intermediate 251

Intermediate 252

Intermediate 253

Intermediate 254

Intermediate 255

Intermediate 256

Intermediate 257

Intermediate 258

Intermediate 259

Intermediate 260

Intermediate 261

Intermediate 262

Intermediate 263

Intermediate 264

Intermediate 265

Intermediate 266

Intermediate 267

Intermediate 268

Intermediate 269

Intermediate 270

Intermediate 271

Intermediate 272

Intermediate 273

Intermediate 274

Intermediate 275

Intermediate 276

Intermediate 277

TABLE 14b Chemical name, NMR chemical shifts and LCMS signal for eachintermediate listed in Table 14a. Intermediate: Name ¹H NMR (400 MHz,CD₃OD) δ ppm LCMS 248: (S)-1-(2-(4-chlorophenyl)thiazol-5- 7.97 (d, J =8.7 Hz, 2H), 7.94 MS m/z yl)ethanamine (s, 1H), 7.52 (d, J = 8.7 Hz,2H), 239.9 (M + H)⁺; 4.95 (m, 1H), 1.78 (d, J = 6.8 Rt-0.59 min Hz, 3H)249: (S)-1-(5-phenylthiophen-2- 7.29 (dd, J = 8.3, 1.2 Hz, 2H), MS m/zyl)ethanamine 7.05 (m, 2 H), 6.99 (m, 2H), 6.89 187.1 (M − NH₂)⁺; (dd, J= 3.8, 0.6 Hz, 1H), 4.45 Rt-0.59 min (m, 1H), 1.41 (d, J = 6.8 Hz, 3H)250: (S)-1-(5-phenylisoxazol-3- 7.87 (m, 2H), 7.55 (m, 3H), 6.95 MS m/zyl)ethanamine (s, 1H), 4.72 (q, J = 6.9 Hz, 1H), 189.2 1.73 (d, J = 6.9Hz, 3H) (M + H)⁺; Rt-0.50 min 251:(S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4- 8.43 (s, 1H), 7.87 (s, 1H), 7.78MS m/z yl)ethanamine (d, J = 9.0 Hz, 2H), 7.51 (d, J = 223.1 (M + H)⁺;9.0 Hz, 2H), 4.61 (q, J = 6.9 Hz, Rt-0.54 min 1H), 1.72 (d, J = 6.9 Hz,3H) 252: (S)-1-(5-(4-fluorophenyl)isoxazol-3- 7.92 (dd, J = 9.0, 5.2 Hz,2H), MS m/z yl)ethanamine 7.30 (t, J = 8.8 Hz, 2H), 6.92 (s, 207.1 (M +H)⁺; 1H), 4.71 (q, 7.0 Hz, 1H), 1.72 Rt-0.51 min (d, J = 7.0 Hz, 3H)253: (S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4- 8.39 (s, 1H), 7.86 (s, 1H),7.78 MS m/z yl)ethanamine (dd, J = 9.2, 4.6 Hz, 2H), 7.25 207.1 (M +H)⁺; (dd, J = 9.1, 8.4 Hz, 2H), 4.60 Rt-0.46 min (q, J = 6.9 Hz, 1H),1.71 (d, J = 6.9 Hz, 3H) 254: (S)-1-(5-(pyridin-2-yl)thiophen-2-8.73-8.78 (m, 1 H), 8.57 (td, MS m/z yl)ethanamine J = 8.0, 1.6 Hz, 1H), 8.31 (d, 206.0 (M + H)⁺; J = 8.3 Hz, 1 H), 8.03 (d, J = 4.0 Rt-0.35min Hz, 1 H), 7.92 (ddd, J = 7.5, 6.0, 1.1 Hz, 1 H), 7.50 (dd, J = 4.0,0.6 Hz, 1 H), 4.91-4.98 (m, 1 H) 1.80 (d, J = 6.8 Hz, 3 H) 255:(S)-1-(5-(morpholinomethyl)isoxazol-3- 6.97 (s, 1H), 4.72 (m, 3H), 3.96MS m/z yl)ethanamine (m, 4H), 3.38 (m, 4H), 1.70 (d, 212.1 (M + H)⁺; J =7.0 Hz, 3H) Rt-0.14 min 256: (S)-1-(2-morpholinothiazol-5- 7.56 (s, 1H),4.78 (quin, J = 6.8 MS m/z yl)ethanamine Hz, 1H), 3.88 (m, 4H), 3.68 (m,197.0 (M − NH₂)⁺; 4H), 1.71 (d, J = 6.9 Hz, 3H) Rt-0.26 min 257:(S)-1-(2-(pyridin-2-yl)thiazol-5- 8.68 (m, 1H), 8.30 (m, 1H), 8.17 MSm/z yl)ethanamine (m, 1H), 8.09 (m, 1H), 7.66 (m, 189.0 (M − NH₂)⁺; 1H),4.99 (q, J = 7.1 Hz, 1H), Rt-0.39 min 1.80 (d, J = 6.9 Hz, 3H) 258:(S)-1-(2-(pyridin-3-yl)thiazol-5- 9.49 (d, J = 2.0 Hz, 1H), 9.14 MS m/zyl)ethanamine (m, 1H), 8.96 (m, 1H), 8.23 189.0 (M − (ddd, J = 8.3, 5.8,0.7 Hz, 1H), NH₂)⁺; Rt- 8.17 (d, J = 0.7 Hz, 1H), 5.04 0.25 min (q, J =6.9 Hz, 1H), 1.82 (d, J = 6.9 Hz, 3H) 259:(S)-1-(2-(pyridin-4-yl)thiazol-5- 8.97 (d, J = 6.9 Hz, 2H), 8.62 MS m/zyl)ethanamine (d, J = 6.9 Hz, 2H), 8.29 (d, J = 189.0 (M − NH₂)⁺; 0.6Hz, 1H), 5.08 (q, J = 6.8 Hz, Rt-0.24 min 1H), 1.84 (d, J = 6.9 Hz, 3H)260: (S)-1-(2-(4- 8.09 (d, J = 7.7 Hz, 2H), 7.99 MS m/z(difluoromethyl)phenyl)thiazol-5- (s, 1H), 7.68 (d, J = 7.7 Hz, 2H),256.0 (M + H)⁺; yl)ethanamine 6.84 (t, J = 56 Hz, 1H), 4.96 (m, Rt-0.56min 1H), 1.78 (d, J = 6.9 Hz, 3H) 261:(S)-1-(2-(6-methylpyridin-3-yl)thiazol-5- 9.30 (d, J = 2.0 Hz, 1H), 8.98MS m/z yl)ethanamine (dd, J = 8.5, 2.0 Hz, 1H), 8.14 220.1 (M + H)⁺; (s,1H), 8.06 (d, J = 8.5 Hz, 1H), Rt-0.27 min 5.03 (q, J = 6.9 Hz, 1H),2.87 (s, 3H), 1.82 (d, J = 6.9 Hz, 3H) 262:(S)-1-(2-(6-(trifluoromethyl)pyridin-3- 9.31 (d, J = 2.1 Hz, 1H), 8.59MS m/z yl)thiazol-5-yl)ethanamine (dd, J = 8.2, 1.7 Hz, 1H), 8.10 274.0(M + H)⁺; (s, 1H), 7.98 (d, J = 8.3 Hz, 1H), Rt-0.51 min 5.01 (q, J =6.8 Hz, 1H), 1.81 (d, J = 6.8 Hz, 3H) 263:(S)-1-(2-(2-(trifluoromethyl)pyridin-4- 8.87 (d, J = 5.1 Hz, 1H), 8.34MS m/z yl)thiazol-5-yl)ethanamine (dd, J = 1.5, 0.7 Hz, 1H), 8.17 274.0(M + H)⁺; (m, 1H), 5.02 (q, J = 6.9 Hz, Rt-0.51 min 1H), 1.82 (d, J =6.9 Hz, 3H) 264: (R)-1-(5-(morpholinomethyl)isoxazol-3- 7.01 (s, 1H),4.74 (m, 3H), 4.00- MS m/z yl)ethanamine 3.86 (br m, 4H), 3.45-3.37212.2 (M + H)⁺; (br m, 4H), 1.70 (d, J = 6.9 Hz, Rt-0.14 min 3H) 265:(S)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)- 9.29 (d, J = 2.4 Hz, 1H),8.56 MS m/z 1H-pyrazol-3-yl)ethanamine (d, J = 2.6 Hz, 1H), 8.47 (dd,257.0 (M + H)⁺; J = 8.6, 2.5 Hz, 1H), 7.98 (d, J = Rt-0.12 min 8.6 Hz,1H), 6.73 (d, J = 2.6 Hz, 1H), 4.68 (q, J = 7.0 Hz, 1H), 1.72 (d, J =6.9 Hz, 3H) 266: (S)-1-(1-(4-chlorophenyl)-2-methyl-1H- 7.83 (d, J = 0.7Hz, 1H), 7.72 MS m/z imidazol-4-yl)ethanamine (m, 2H), 7.63 (m, 2H),4.75 (q, 236.1 (M + H)⁺; J = 7.0 Hz, 1H), 2.63 (s, 3H), 1.79 Rt-0.45 min(d, J = 7.0 Hz, 3H) 267: (S)-1-(2-fluoro-4-(1- MS m/zmethylcyclopropyl)phenyl)ethanamine 194.1 (M + H)+, Rt 0.60 min. 268:(S)-1-(4-(1-ethoxycyclopropyl)-2- (D2O) 0.98 (s, 1 H) 1.03-1.08 MS m/zfluorophenyl)ethanamine (m, 2H) 1.14 (t, J = 7.09 Hz, 1 H) 224.1 (M +H)+, 1.25-1.30 (m, 2 H) 1.64 (d, Rt 0.56 min. J = 6.99 Hz, 3 H)3.45-3.59 (m, 2 H) 7.16 (dd, J = 5.58, 1.47 Hz, 1 H) 7.17-7.21 (m, 1 H)7.40- 7.48 (m, 1 H) 269: (S)-1-(4-(1-aminoethyl)-3- MS m/zfluorophenyl)cyclopropanecarbonitrile 205.1 (M + H)+, Rt 0.44 min. 270:(S)-1-(2-fluoro-4- MS m/z isopropylphenyl)ethanamine 182.1 (M + H)+, Rt0.59 min. 271: (S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol- MS m/z4-yl)phenyl)ethanamine 220.1 (M + H)+, Rt 0.43 min. 272:(S)-1-(4-(1-methyl-1H-pyrazol-4- MS m/z yl)phenyl)ethanamine 185.1 (M +H)+, Rt 0.41 min. 273: (S)-1-(2-fluoro-4-(1H-pyrazol-4- (D2O) 1.66 (d, J= 6.99 Hz, 3 H) MS m/z yl)phenyl)ethanamine 4.76-4.82 (m, 1 H) 7.39-7.52206.1 (M + H)+, (m, 3 H) 8.16 (s, 2 H) Rt 0.37 min. 274:(S)-1-(2-fluoro-4- (D2O) 1.67 (d, J = 6.94 Hz, 3 H) MS m/z(trifluoromethyl)phenyl)ethanamine 4.84 (q, J = 6.94 Hz, 1 H) 7.54-208.0 (M + H)+, 7.70 (m, 3 H) Rt 0.51 min. 275:(S)-4-(1-aminoethyl)-2-chloro-N- MS m/z cyclopentylbenzamide 267.0 (M +H)+, Rt 0.50 min. 276: (S)-1-(2,5-difluoro-4-(1-methyl-1H- (D2O) 1.65(d, J = 6.94 Hz, 3 H) MS m/z pyrazol-4-yl)phenyl)ethanamine 3.53 (q, J =7.11 Hz, 1 H) 3.91 239.1 (M + H)+, (s, 3 H) 7.28 (dd, J = 11.10, 6.26 Rt0.45 min. Hz, 1 H) 7.44 (dd, J = 11.18, 6.24 Hz, 1 H) 7.94 (s, 1 H) 8.06(d, J = 1.86 Hz, 1 H) 277: (S)-1-(1-(4-chlorophenyl)-1H-imidazol- (D2O)1.74 (d, J = 6.65 Hz, 3 H) MS m/z 4-yl)ethanamine 4.76-4.85 (m, 1 H)7.61 (q, 222.1 (M + H)+, J = 9.00 Hz, 4 H) 8.00 (s, 1 H) Rt 0.44 min.9.04 (s, 1 H)

Intermediate 278:(S)-1-(2-fluoro-4-(2-fluoropropan-2-yl)phenyl)ethanamine

Step 1

To a round bottom flask containing(R)—N—((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(1.02 g, 3.60 mmol) was added dioxane (7 mL). To this homogenoussolution was then added HCl in Dioxane (1.80 mL, 7.20 mmol, 4 M).Resulting reaction mixture allowed to stir 10 min at room temperature.Volatiles removed. Et₂O was added and mixture sonicated briefly.Volatiles removed again. Et₂O was added and the solid collected andwashed with Et₂O to afford a white HCl salt of(S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethanamine (742 mg, 3.44 mmol,96% yield). ¹H NMR (400 MHz, D₂O) δ 1.65 (d, J=6.94 Hz, 3H) 2.12 (s, 3H)5.23 (s, 1H) 5.50 (s, 1H) 7.37 (d, J=13.06 Hz, 1H) 7.43 (m, 2H). LCMSm/z 163.2 (deamino fragment) (M+H)⁺, Rt 0.56 min.

Step 2

To a RBF containing (S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethanamine(742 mg, 3.44 mmol) was added NMP (7 mL). To this solution was thenadded TEA (959 μl, 6.88 mmol) followed by the addition of Di-tert-butyldicarbonate (976 mg, 4.47 mmol). Resulting reaction mixture allowed tostir 2 hr at room temperature. Reaction mixture was diluted with waterand extracted with EtOAc. Organic phases combined, washed with water,brine, dried (Na₂SO₄), filtered and concentrated onto silica gel. Silicagel column chromatography (EtOAc/Heptanes 0 to 100%) provided(S)-tert-butyl (1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)carbamate(1.28 g, 4.58 mmol, 133% yield) as a white crystalline. ¹H NMR (400 MHz,CDCl₃) δ 1.40-1.48 (m, 12H) 2.12 (d, J=0.44 Hz, 3H) 4.98 (br. s., 2H)5.10-5.12 (m, 1H) 5.37 (s, 1H) 7.11-7.16 (m, 1H) 7.19-7.24 (m, 2H). LCMSm/z 163.0 (deamino fragment) (M+H)⁺, Rt 1.13 min.

Step 3

To a round bottom flask containing (S)-tert-butyl(1-(2-fluoro-4-(prop-1-en-2-yl)phenyl) ethyl)carbamate (1.28 g, 4.58mmol) was added DCM (23 mL). The homogenous solution was cooled to −70°C. in a acetone/dry ice bath. Ozone (g) was then gently bubbled throughthe solution for 25 min at which time the solution becomes pale blue incolor. Dimethyl sulfide (1.02 mL, 13.8 mmol) was then added to the coldsolution and mixture gradually allowed to warm to room temperature andstirred for 30 min. Reaction mixture was diluted with a water. Phasespartitioned. Aqueous phase extracted with DCM. Organic phases combined,washed with brine, dried (Na₂SO₄), filtered and concentrated onto silicagel. Silica gel column chromatography (EtOAc/Heptane 0 to 60%) provided(S)-tert-butyl (1-(4-acetyl-2-fluorophenyl)ethyl)carbamate (296 mg, 1.05mmol, 23% yield) as a colorless oil that crystallizes upon standing. ¹HNMR (400 MHz, CDCl₃) δ 1.38-1.49 (m, 12H) 2.59 (s, 3H) 5.01 (br. s., 1H)7.40 (t, J=7.65 Hz, 1H) 7.62 (dd, J=11.20, 1.57 Hz, 1H) 7.71 (dd,J=7.95, 1.54 Hz, 1H). LCMS m/z 267.1 (carboxylic acid fragment+CH₃CN)(M+H)⁺, Rt 0.89 min.

Step 4

To a solution of (S)-tert-butyl(1-(4-acetyl-2-fluorophenyl)ethyl)carbamate (296 mg, 1.05 mmol) in DCM(5.2 mL), cooled to 0° C. (water/ice bath) under N₂, was added 3M MeMgBr(1.4 mL, 4.21 mmol) in diethyl ether. Reaction mixture allowed to stirfor 5 min at 0° C. Then gradually allowed to warm to room temperatureand stirred for 30 min at room temperature. Reaction mixture was cooledto 0° C. then quenched with the slow addition of a saturated solution ofNH₄Cl and diluted with DCM. Phases partitioned, aqueous phase extractedwith DCM and the organic layers combined washed with water, brine, dried(Na₂SO₄), filtered and concentrated to (S)-tert-butyl(1-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)ethyl)carbamate (288 mg,0.97 mmol, 92% yield) afford as a colorless oil which slowlycrystallizes upon standing. ¹H NMR (400 MHz, CDCl₃) δ 1.39-1.48 (m, 12H)1.57 (s, 6H) 7.15-7.25 (m, 2H) 7.31-7.36 (m, 1H).

Step 5

To a RBF containing (S)-tert-butyl(1-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)ethyl) carbamate (288 mg,0.97 mmol) was added DCM (5 mL) the resulting colorless solution wascooled to −70° C. in a dry ice/acetone bath. To this cold solution underN₂ was then added DAST (0.26 mL, 1.94 mmol) resulting reaction mixtureallowed to stir 1 hr at −70° C. To the cold solution was added ice andresulting mixture allowed to warm to room temperature. Mixture dilutedwith DCM, phases partioned and the aqueous phase extracted with DCM.Organic layers combined, washed with brine, dried (Na₂SO₄), filtered andconcentrated to onto silica gel. Silica gel column chromatography(EtOAc/Heptane 0 to 50%) provided (S)-tert-butyl(1-(2-fluoro-4-(2-fluoropropan-2-yl)phenyl)ethyl)carbamate (126 mg, 0.42mmol, 44% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.39-1.49(m, 12H) 1.66 (d, J=21.52 Hz, 6H) 4.97 (br. s., 1H) 7.04-7.12 (m, 2H)7.22-7.26 (m, 1H). LCMS m/z 285.1 (carboxylic acid fragment+CH₃CN)(M+H)⁺, Rt 1.06 min.

Step 6

To a round bottom flask containing (S)-tert-butyl(1-(2-fluoro-4-(2-fluoropropan-2-yl)phenyl)ethyl)carbamate (126 mg, 0.42mmol) was added HCl in dioxane (2.1 mL, 8.42 mmol). Resulting reactionmixture allowed to stir 1 hr at room temperature. Volatiles wereremoved. Et₂O was then added and the mixture sonicated briefly.Volatiles were once again removed to a afford an HCl salt of(S)-1-(2-fluoro-4-(2-fluoropropan-2-yl)phenyl)ethanamine (104 mg, 0.44mmol, 105% yield) as a white solid. ¹H NMR (400 MHz, D₂O) δ 1.59-1.80(m, 9H) 7.24-7.37 (m, 2H) 7.43-7.56 (m, 1H). LCMS m/z 200.1 (M+H)⁺, Rt0.54 min.

Intermediate 279: (S)-2-(4-(1-aminoethyl)-3-fluorophenyl)propan-2-ol

Step 1

To a microwave vial with stir bar was added(R)—N—((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(1 g, 3.10 mmol) followed by the addition oftributyl(1-ethoxyvinyl)stannane (2.24 g, 6.21 mmol), TEA (1.3 mL, 9.31mmol) and PdCl₂(dppf).CH₂Cl₂ adduct (0.127 g, 0.155 mmol). To the solidswas then added toluene (10 mL). Vial capped and heated by microwaveirradiation at 100° C. for 30 min. To this reaction mixture was added 1ml of TFA to try to convert vinyl ether to the ketone which wasunsuccessful. Resulting reaction mixture allowed to stir 5 min at roomtemperature. Reaction mixture was then quenched with a saturatedsolution of NaHCO₃ to pH 8. Aqueous mixture extracted with EtOAc.Organic phases combined, washed with water, brine, dried (Na₂SO₄),filtered and concentrated onto silica gel. Silica gel columnchromatography (EtOAc/Heptane 40 to 100%) provided(R)—N—((S)-1-(4-(1-ethoxyvinyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(0.60 g, 1.91 mmol, 62% yield) as a yellow viscous residue. ¹H NMR (400MHz, CDCl₃) δ 1.20 (s, 9H) 1.43 (t, J=6.94 Hz, 3H) 1.56-1.63 (m, 5H)3.36 (d, J=3.13 Hz, 1H) 3.92 (q, J=6.96 Hz, 2H) 4.23 (br. s., 1H) 4.65(s, 1H) 4.79-4.91 (m, 1H) 7.30 (s, 2H) 7.40 (d, J=8.02 Hz, 1H).

Step 2

To a round bottom flask containing(R)—N—((S)-1-(4-(1-ethoxyvinyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(600 mg, 1.91 mmol) was added MeOH (19 mL). To this homogenous solutionwas then added HCl (aq) (3.2 mL, 19.1 mmol, 3 M). Resulting reactionmixture was stirred at room temperature for 30 min. Volatiles were thenremoved. Residue triturated with Et₂O to provide(S)-1-(4-(1-aminoethyl)-3-fluorophenyl)ethanone (0.43 g, 1.98 mmol, 103%yield) as a HCl salt. ¹H NMR (400 MHz, D₂O) δ 1.67 (d, J=6.99 Hz, 3H)2.64 (s, 3H) 4.80-4.87 (m, 1H) 7.61 (t, J=7.73 Hz, 1H) 7.77 (dd,J=11.30, 1.66 Hz, 1H) 7.87 (dd, J=8.09, 1.64 Hz, 1H). LCMS m/z 182.0(M+H)⁺, Rt 0.36 min.

Step 3

To a round bottom flask with stir bar was added(S)-1-(4-(1-aminoethyl)-3-fluorophenyl) ethanone (0.43 g, 1.98 mmol)followed by the addition of NMP (9.9 mL). To this solution was thenadded DIEA (0.83 mL, 4.74 mmol) and Di-tert-butyl dicarbonate (0.95 g,4.35 mmol). The resulting reaction mixture allowed to stir 2 hr at roomtemperature. Reaction mixture was diluted with water, extracted withEtOAc. Organic phase washed with water, brine, dried (Na₂SO₄), filteredand concentrated onto silica gel. Silica gel column chromatography(EtOAc/Heptane 0 to 100%) provided (S)-tert-butyl1-(4-acetyl-2-fluorophenyl)ethylcarbamate (369 mg, 1.31 mmol, 66.4%yield) as a colorless oil which crystallizes upon standing. ¹H NMR (400MHz, CDCl₃) δ 1.38-1.49 (m, 12H) 2.59 (s, 3H) 5.01 (br. s., 1H) 7.40 (t,J=7.65 Hz, 1H) 7.62 (dd, J=11.20, 1.57 Hz, 1H) 7.71 (dd, J=7.95, 1.54Hz, 1H). LCMS m/z 267.1 (carboxylic acid fragment+CH₃CN) (M+H)⁺, Rt 0.89min.

Step 4

To a solution of (S)-tert-butyl(1-(4-acetyl-2-fluorophenyl)ethyl)carbamate (200 mg, 0.71 mmol) in DCM(7.1 mL), cooled to 0° C. (water/ice bath) under N₂, was added 3M MeMgBr(10.95 mL, 2.84 mmol) in diethyl ether. Reaction mixture allowed to stirfor 5 min at 0° C. Then gradually allowed to warm to room temperatureand stirred for 30 min at room temperature. Reaction mixture was cooledto 0° C. then quenched with the slow addition of a saturated solution ofNH₄Cl and diluted with DCM. Phases partitioned, aqueous phase extractedwith DCM and the organic layers combined washed with water, brine, dried(Na₂SO₄), filtered and concentrated to (S)-tert-butyl(1-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)ethyl)carbamate (184 mg,0.62 mmol, 87% yield) afford as a colorless oil which slowlycrystallizes upon standing. ¹H NMR (400 MHz, CDCl₃) δ 1.39-1.48 (m, 12H)1.57 (s, 6H) 7.15-7.25 (m, 2H) 7.31-7.36 (m, 1H).

Step 5

To a round bottom flask containing (S)-tert-butyl(1-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)ethyl)carbamate (184 mg,0.62 mmol) and a stir bar was added dioxane (2 mL). To this reactionmixture was then added HCl in dioxane (0.93 ml, 3.71 mmol, 4.0M).Resulting reaction mixture allowed to stir at room temperature for 18hr. Volatiles were then removed. Residue triturated with Et₂O to afford(S)-2-(4-(1-aminoethyl)-3-fluorophenyl)propan-2-ol (142 mg, 0.61 mmol,98% yield) as a HCl salt. ¹H NMR (400 MHz, D₂O) δ 1.53 (s, 6H) 1.64 (d,J=7.04 Hz, 3H) 3.73 (s, 1H) 7.28-7.37 (m, 2H) 7.42-7.48 (m, 1H). LCMSm/z 198.1 (M+H)⁺, Rt 0.37 min.

Intermediate 280:(R)—N—((S)-1-(2,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide

To a mixture of ethyl 2-oxocyclohexanecarboxylate (58.0 mg, 0.341 mmol),(R)—N—((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(580 mg, 1.705 mmol), Cs₂CO₃ (1555 mg, 4.77 mmol), copper(I) iodide(32.5 mg, 0.170 mmol) was added 2,2,2-trifluoroethanol (871 μl, 11.93mmol). The reaction was sealed and heated at 78° C. for 24 hours. LCMSindicated complete conversion to product. The reaction mixture was thencooled to room temperature and diluted with EtOAc (20 mL). The mixturewas filtered through a pad of celite and the pad was rinsed with EtOAc(20 mL). The organic was washed with water (2×15 mL), dried (Na₂SO₄) andconcentrated. The residue was then filtered through a pad of silica gel(30 g) with EtOAc/heptane (1:3) to give crude(R)—N—((S)-1-(2,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide(0.601 g). LCMS (B) m/z 360.1 (M+H)⁺

Intermediate 281:(S)-1-(2,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine

To a solution of(R)—N—((S)-1-(2,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide(0.601 g, 1.672 mmol) in dioxane (10 ml) was added dropwise HCl (0.836ml, 3.34 mmol). The reaction was stirred at room temperature for 30minutes. LCMS indicated complete conversion to product. The reactionmixture was concentrated and DCM (20 mL) and saturated NaHCO₃ solution(10 mL) was added to the residue. The mixture was stirred for 10 minutesand phases were separated. Aqueous layer was then extracted with DCM(2×10 mL), and the combined organic was dried (Na₂SO₄) and concentratedto give crude product. LCMS (B) m/z 256.2 (M+H)⁺

The intermediates in Table 15a were prepared using a method similar tothat described for the preparation of Intermediate 281.

TABLE 15a

Intermediate 282

Intermediate 283

Intermediate 284

TABLE 15b Chemical name and analytical data for each intermediate listedin Table 15a. Intermediate: Name Analytical data 282:(S)-1-(4-bromo-2,5- LCMS m/z (M + H)⁺ difluorophenyl)ethanamine 239.2,RT 0.52 min. 283: (S)-1-(2-fluoro-4-(2,2,2- LCMS m/z (M + H)⁺trifluoroethoxy)phenyl)ethanamine 238.3, RT 0.57 min. 284:(S)-1-(3-fluoro-4-(2,2,2- LCMS m/z (M + H)⁺trifluoroethoxy)phenyl)ethanamine 238.3, RT 0.58 min.

Intermediate 285:(R,E)-N-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)methylene)-2-methylpropane-2-sulfinamide

To a mixture of 1H-pyrazole-3-carbaldehyde (1.52 g, 15.82 mmol),1-chloro-4-iodobenzene (5.66 g, 23.73 mmol),(1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.450 g, 3.16 mmol),copper(I) iodide (0.151 g, 0.791 mmol) and K₂CO₃ (4.37 g, 31.6 mmol) wasadded toluene (20 mL). The reaction was sealed and heated to 110° C. for18 hours. The reaction mixture was then cooled to room temperature anddiluted with water (50 mL), and extracted with EtOAc (3×30 mL). Thecombined organic was then dried (Na₂SO₄) and concentrated to give crude1-(4-chlorophenyl)-1H-pyrazole-3-carbaldehyde (1.86 g, 9.0 mmol), towhich was added (R)-2-methylpropane-2-sulfinamide (1.20 g, 9.90 mmol),CuSO4 (2.155 g, 13.50 mmol) and DCE (30 ml). The reaction was sealed,heated at 60° C. for 18 hours. A dark green suspension resulted. Thereaction mixture was then cooled to 20° C., filtered through a pad ofcelite, rinsed with DCM. The solution was then concentrated to givefinal crude product as a light green oil. The residue was purified viasilica gel chromatography (EtOAc/Heptane). LCMS (B) m/z 310.3 (M+H)⁺

Intermediate 286:(R)—N—((R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of(R,E)-N-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)methylene)-2-methylpropane-2-sulfinamide(2.12 g, 6.84 mmol) in DCM (40 ml) at −40° C. was added methylmagnesiumbromide (9.12 ml, 27.4 mmol). The reaction was stirred at −40° C. for 3hours. The reaction mixture was then quenched with saturated NH₄Clsolution (20 mL). The aqueous layer was adjusted to pH=8 with HCl (1M)and extracted with DCM (2×200 mL). The combined organic was dried(Na₂SO₄) and concentrated. The residue was then purified via silica gelchromatography (EtOAC/heptane) to give(R)—N—((R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide(1.11 g). LCMS (B) m/z 326.3 (M+H)⁺

Intermediate 287: (R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethanamine

To a solution of(R)—N—((R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide(0.98 g, 3.01 mmol) in dioxane (10 ml) was added dropwise HCl (1.504 ml,6.01 mmol). The reaction was stirred at room temperature for 30 minutes.LCMS indicated complete conversion to product. The reaction mixture wasconcentrated and DCM (20 mL) and saturated NaHCO₃ solution (10 mL) wasadded to the residue. The mixture was stirred for 10 minutes and phaseswere separated. Aqueous layer was then extracted with DCM (2×10 mL), andthe combined organic was dried (Na₂SO₄) and concentrated to give product(0.556 g). LCMS (B) m/z 222.2 (M+H)⁺

Intermediate 288:(R)—N—((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of(R,E)-N-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)methylene)-2-methylpropane-2-sulfinamide(2.12 g, 6.84 mmol) in DCM (40 ml) at −40° C. was added methylmagnesiumbromide (9.12 ml, 27.4 mmol). The reaction was stirred at −40° C. for 3hours. The reaction mixture was then quenched with saturated NH₄Clsolution (20 mL). The aqueous layer was adjusted to pH=8 with HCl (1M)and extracted with DCM (2×200 mL). The combined organic was dried(Na₂SO₄) and concentrated. The residue was then purified via silica gelchromatography (EtOAC/heptane) to give(R)—N—((R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide(1.01 g). LCMS (B) m/z 326.3 (M+H)⁺

Intermediate 289: (S)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethanamine

To a solution of(R)—N—((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide(0.98 g, 3.01 mmol) in dioxane (10 ml) was added dropwise HCl (1.504 ml,6.01 mmol). The reaction was stirred at room temperature for 30 minutes.LCMS indicated complete conversion to product. The reaction mixture wasconcentrated and DCM (20 mL) and saturated NaHCO₃ solution (10 mL) wasadded to the residue. The mixture was stirred for 10 minutes and phaseswere separated. Aqueous layer was then extracted with DCM (2×10 mL), andthe combined organic was dried (Na₂SO₄) and concentrated to give crudeproduct (0.501 g). LCMS (B) m/z 222.2 (M+H)⁺

The intermediates in Table 16a were prepared using a method similar tothat described for the preparation of Intermediate 289

TABLE 16a

Intermediate 290

Intermediate 291

Intermediate 292

Intermediate 293

Intermediate 294

Intermediate 295

TABLE 16b Chemical name and analytical data for each intermediate listedin Table 16a. Intermediate: Name Analytical data 290:(S)-1-(5-bromo-3-fluoropyridin-2- LCMS(B) m/z (M + H)⁺ yl)ethanamine219.0, 221.0, RT 0.37 min. 291: (R)-1-(5-bromo-3-fluoropyridin-2-LCMS(B) m/z (M + H)⁺ yl)ethanamine 219.0, 221.0, RT 0.38 min. 292:(S)-1-(5-bromopyridin-2-yl)ethanamine LCMS(B) m/z (M + H)⁺ 201.0, 203.0,RT 0.37 min. 293: (R)-1-(5-bromopyridin-2-yl)ethanamine LCMS(B) m/z (M +H)⁺ 201.0, 203.0, RT 0.40 min. 294: (S)-1-(3,5-dichloropyridin-2-LCMS(B) m/z (M + H)⁺ yl)ethanamine 191.1, RT 0.45 min. 295:(R)-1-(3,5-dichloropyridin-2- LCMS(B) m/z (M + H)⁺ yl)ethanamine 191.1,RT 0.44 min.

Intermediate 296:(R)—N—((S)-1-(2,5-difluoro-4-(2-(trifluoromethyl)pyridin-4-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of(R)—N—((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(230 mg, 0.676 mmol) in dioxane/H₂O (5 mL/lmL) was added sodium2′-(dicyclohexylphosphino)-2,6-dimethoxy-[1,1′-biphenyl]-3-sulfonate(34.7 mg, 0.068 mmol), (2-(trifluoromethyl)pyridin-4-yl)boronic acid(194 mg, 1.014 mmol), K₂CO₃ (234 mg, 1.690 mmol) followed by Pd₂dba₃(31.0 mg, 0.034 mmol). The reaction mixture was sealed and heated to110° C. and stirred for 2 hours. LCMS show complete conversion. Thereaction mixture was then cooled to room temperature and diluted withEtOAc (20 mL) and water (10 mL). The aqueous layer was then extractedwith EtOAc (2×20 mL). The combined organic was then concentrated. Theresidue was purified by silica gel chromatography (50% heptane in EtOActo 10% MeOH in EtOAc) to give product. (0.25 g). LCMS (B) m/z 407.6(M+H)⁺

Intermediate 297:(S)-1-(2,5-difluoro-4-(2-(trifluoromethyl)pyridin-4-yl)phenyl)ethanamine

To a solution of(R)—N—((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide(0.98 g, 3.01 mmol) in dioxane (10 ml) was added dropwise HCl (1.504 ml,6.01 mmol). The reaction was stirred at room temperature for 30 minutes.LCMS indicated complete conversion to product. The reaction mixture wasconcentrated and DCM (20 mL) and saturated NaHCO₃ solution (10 mL) wasadded to the residue. The mixture was stirred for 10 minutes and phaseswere separated. Aqueous layer was then extracted with DCM (2×10 mL), andthe combined organic was dried (Na₂SO₄) and concentrated to give crudeproduct (0.501 g). LCMS (B) m/z 303.2 (M+H)⁺

The intermediates in Table 17a were prepared using a method similar tothat described for the preparation of Intermediate 297

TABLE 17a

Intermediate 298

Intermediate 299

Intermediate 300

TABLE 17b Chemical name and analytical data for each intermediate listedin Table 17a. Intermediate: Name Analytical data 298:(S)-1-(2,5-difluoro-4-(2-methyl- LCMS(B) m/z (M + H)⁺ 249.2,pyridin-4-yl)phenyl)ethanamine RT 0.34 min. 299:(S)-1-(2,5-difluoro-4-(6-methyl- LCMS(B) m/z (M + H)⁺ 249.1,pyridin-3-yl)phenyl)ethanamine RT 0.32 min. 300:(S)-1-(2,5-difluoro-4-(6- LCMS(B) m/z (M + H)⁺ 303.2,(trifluoromethyl)pyridin-3- RT 0.64 min. yl)phenyl)ethanamine

Intermediate 301:(R)—N—((S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

To a solution ofdi-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine(80 mg, 0.166 mmol) in toluene/dioxane (8 mL/2 mL) was added Pd₂dba₃ (60mg, 0.066 mmol). The reaction mixture was sealed and heated to 120° C.and stirred for 5 minutes. The reaction was cooled to room temperatureand 4-methyl-1H-imidazole (157 mg, 1.910 mmol),(R)—N—((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(500 mg, 1.470 mmol) and K₃PO₄ (624 mg, 2.94 mmol) was added to thereaction mixture. The reaction was sealed and heated to 120° C. for 2hours. LCMS show complete conversion. The reaction mixture was thencooled to room temperature and diluted with EtOAc (20 mL) and water (10mL). The aqueous layer was then extracted with EtOAc (2×20 mL). Thecombined organic was then concentrated. The residue was purified bysilica gel chromatography (50% heptane in EtOAc to 10% MeOH in EtOAc) togive (S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethanamine(500 mg). LCMS (B) m/z 342.6 (M+H)⁺

Intermediate 302:(S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethanamine

To a solution of(R)—N—((S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(500 mg) in MeOH (10 mL) was added dropwise HCl (732 μl, 2.93 mmol). Thereaction was stirred at room temperature for 30 minutes. LCMS indicatedcomplete conversion to product. The reaction mixture was concentratedand DCM (20 mL) and saturated NaHCO₃ solution (10 mL) was added to theresidue. The mixture was stirred for 10 minutes and phases wereseparated. Aqueous layer was then extracted with DCM (2×10 mL), and thecombined organic was dried (Na₂SO₄) and concentrated to give(S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethanamine (330mg). LCMS (B) m/z 238.1 (M+H)⁺

Intermediate 303: (S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethanamineHydrochloride

Step 1: Preparation of tert-butyl 4-formyl-1H-imidazole-1-carboxylate

To di-tert-butyl dicarbonate (23.25 g, 107 mmol) and1H-imidazole-4-carbaldehyde (9.75 g, 101 mmol) in THF (200 mL) was addedDMAP (100 mg, 0.819 mmol). The reaction was stirred for two hours. Thereaction mixture was then diluted with saturated NaHCO₃ solution/EtOAc(100 mL/100 mL). The aqueous was then extracted with EtOAc (2×100 mL)and the combined organic was dried (Na₂SO₄) and concentrated to givecrude product (19.9 g). LCMS (B) m/z 197.2 (M+H)⁺

Step 2: Preparation of (S,E)-tert-butyl4-(((tert-butylsulfinyl)imino)methyl)-1H-imidazole-1-carboxylate

To CuSO₄ (24.28 g, 152 mmol) and tert-butyl4-formyl-1H-imidazole-1-carboxylate (19.9 g, 101 mmol) in DCE (100 mL)was added (S)-2-methylpropane-2-sulfinamide (13.52 g, 112 mmol). Thereaction was heated to 65° C. for 18 hours. The reaction mixture wasthen cooled to room temperature and filtered through a pad of celite.The pad was rinsed with DCM (200 mL) and the filtrated was concentrated.The residue was then run through a pad of silica gel with heptane/EtOAc(3:1) as eluent. The filtrate was concentrated to give crude(S,E)-tert-butyl4-(((tert-butylsulfinyl)imino)methyl)-1H-imidazole-1-carboxylate (22 g).LCMS (B) m/z 300.2 (M+H)⁺

Step 3: Preparation of(S,E)-N-((1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide

To (S,E)-tert-butyl4-(((tert-butylsulfinyl)imino)methyl)-1H-imidazole-1-carboxylate (18.61g, 62.2 mmol) in DCM (250 mL) at −70° C. was added dropwisemethylmagnesium bromide (83 mL, 249 mmol) in Et₂O. The reaction wasstirre at −70° C. for 4 hours. The reaction mixture was then warmed to−40° C. and stirred for one hour. The reaction was then quenched withcautious addition of HCl (1N). Cold bath was removed and while withstirring the aqueous layer was adjusted pH=8. The aqueous layer wasseparated and extracted with DCM (3×100 mL). The combined organic wasdried (Na₂SO₄) and concentrated to give crude product as a mixture oftert-butyl4-((S)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)-1H-imidazole-1-carboxylateand (S,E)-N-((1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide,to which was added DCM (300 mL) at 0° C. and formic acid (100 mL, 2651mmol). The cold bath was then removed and the reaction was stirred for 2hours. The reaction mixture was then concentrated under reduce pressureto remove DCM and formic acid. The residue was diluted with DCM (400 mL)and washed with saturated Na₂CO₃ aqueous solution (2×200 mL). Thecombined aqueous was extracted with DCM (2×200 mL). The combined organicwas then dried (Na₂SO₄) and concentrated to give(S,E)-N-((1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide(12.5 g). LCMS (B) m/z 216.1 (M+H)⁺

Step 4: Preparation of(S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethanamine Hydrochloride

To a 200 mL RBF was added toluene/dioxane (80 ml/20 mL). The flask wascooled to 0° C. and the mixture of solvents was evacuated under highvacuum for 2 minutes and then recharged with argon. The process wasrepeated three more times. This solvent was then used for the reaction.

A vial containingdi-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine(55.8 mg, 0.116 mmol) and Pd₂(dba)₃ (42 mg, 0.046 mmol) was evacuatedunder high vacuum for 1 minute and then recharged with argon. Theprocess was repeated three more times and the toluene/dioxane solvent(10 mL) prepared as above was added followed by the palladium/ligandcomplex prepared as above was then added to the reaction vial containingthe other starting materials. The reaction mixture was sealed and heatedto 120° C. and stirred for 5 minutes. The reaction was cooled to roomtemperature.

A separate reaction vial was charged with(S,E)-N-((1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (500mg, 2.322 mmol), 1-bromo-4-fluorobenzene (447 mg, 2.55 mmol) and K₃PO₄(986 mg, 4.64 mmol). The vial was evacuated under high vacuum for 1minute and then recharged with argon. The process was repeated threemore times and the palladium/ligand complex prepared as above was thenadded to the reaction vial containing the other starting materials. Thereaction was sealed and heated to 120° C. for 18 hours. LCMS showcomplete conversion. The reaction mixture was then cooled to roomtemperature and filtered through a pad of celite. The solid was rinsedwith EtOAc (30 mL). The filtrate was then washed with water (2×20 mL).The aqueous layer was then extracted with EtOAc (20 mL). The combinedorganic was then concentrated. The residue was purified via silica gelchromatography (EtOAc/Heptane 70%-100% with 5% MeOH) to give(S)—N—((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide.LCMS (B) m/z 310.2 (M+H)⁺

To the above intermediate product was added MeOH (5 mL) and HCl (4M indioxane, 1 mL). The reaction mixture was stirred for one hour and LCMSshowed complete conversion, The mixture was then concentrated to give(S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethanamine hydrochloride (300mg). LCMS (B) m/z 206.0 (M+H)⁺

Intermediate 304: 5-chloro-6-(1,1-difluoroethyl)nicotinaldehyde

Step 1: Preparation of Ethyl 5,6-dichloronicotinate

To a solution of 5,6-dichloronicotinic acid (20.01 g, 104 mmol) in EtOH(500 mL) at 20° C. was added chlorotrimethylsilane (132 mL, 1042 mmol).The reaction was stirred for 72 hours. The reaction mixture was thenconcentrated and diluted with EtOAc (500 mL), and washed with saturatedNaHCO₃ (2×100 mL) and brine (100 mL). The organic was then dried(Na₂SO₄) and concentrated under reduced pressure to give final crudeproduct (21.25 g). LCMS m/z 220.1 (M+H)⁺, Rt 0.94 min.

Step 2: Preparation of Ethyl 6-acetyl-5-chloronicotinate

To a suspension of ethyl 5,6-dichloronicotinate (5.26 g, 23.90 mmol) andtetraethylammonium-chloride (11.88 g, 71.7 mmol) in MeCN (50 mL) wasadded tributyl(1-ethoxyvinyl)stannane (9.50 g, 26.3 mmol) andPdCl₂(PPh₃)₂ (0.671 g, 0.956 mmol). The reaction was sealed, heated at80° C. for 5 hours. A dark color clear solution resulted. The reactionmixture was then cooled to 20° C., concentrated and diluted with EtOAc(200 mL), and washed with water (50 mL) and brine (50 mL). The organicwas then dried (Na₂SO₄) and concentrated to give crude ethyl5-chloro-6-(1-ethoxyvinyl)nicotinate. The residue was then dissolved inTHF (100 mL) and HCl (20 mL, 3M in H₂O) was added. The reaction mixturewas stirred at 20° C. for 5 hours, and saturated NaHCO₃ solution wasadded until pH=8. The mixture was then diluted with EtOAc (200 mL) andwater (50 mL). The phases were separated and the aqueous layer wasextracted with EtOAc (2×50 mL). The combined organics was washed withbrine (20 mL), dried (Na₂SO₄) and concentrated to afford the desiredproduct (3.56 g). LCMS m/z 228.5 (M+H)⁺, Rt 0.83 min.

Step 3: Preparation of Ethyl 5-chloro-6-(1,1-difluoroethyl)nicotinate

To a solution of ethyl 6-acetyl-5-chloronicotinate (3.01 g, 13.22 mmol)in CHCl3 (7 mL) was added DAST (5.20 mL, 39.7 mmol) and ethanol (0.061g, 1.32 mmol). The reaction was sealed, heated at 60° C. for 24 hours. Adark color clear solution resulted. The reaction mixture was then cooledto 20° C., and added cautiously with cold concentrated NaHCO₃ aqueoussolution (50 mL). The aqueous layer was extracted with DCM (2×100 mL).The combined organic was then dried (Na₂SO₄) and concentrated. Theresidue was purified via silica gel flash chromatography (0-20 percentEtOAc-Hexanes) to afford the desired product as yellow oil (2.88 g).LCMS m/z 250.1 (M+H)⁺, Rt 0.99 min.

Step 4: Preparation of(5-chloro-6-(1,1-difluoroethyl)pyridin-3-yl)methanol

To a solution of ethyl 5-chloro-6-(1,1-difluoroethyl)nicotinate (2.68 g,10.74 mmol) in Et₂O (40 mL) was added LiBH₄ (0.351 g, 16.10 mmol),followed by dropwise addition of methanol (0.653 mL, 16.10 mmol). Thereaction was refluxed at 40° C. for one hour. The reaction mixture wasthen cooled to 0° C., and quenched with HCl (1M) until pH=2 for aqueouslayer. The phases were separated and the aqueous layer was extractedwith DCM (3×50 mL). The organic was then dried (Na₂SO₄) and concentratedunder reduced pressure to give final crude product (2.12 g). LCMS m/z208.0 (M+H)⁺, Rt 0.63 min.

Step 5: Preparation of 5-chloro-6-(1,1-difluoroethyl)nicotinaldehyde

To a solution of (5-chloro-6-(1,1-difluoroethyl)pyridin-3-yl)methanol(2.12 g, 10.21 mmol) in DCM (100 ml) was added PCC (3.30 g, 15.32 mmol).The reaction was stirred at 20° C. for 3 hours. A dark color suspensionresulted. LCMS showed clean conversion to the product. The reactionmixture was then filtered through a pad of celite, and washed with DCM(200 mL). The filtrate was then concentrated to give crude product (1.78g). LCMS m/z 224.0 (M+H2O+H)⁺, Rt 0.72 min.

Intermediate 305: 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinaldehyde

Step 1: Preparation of Ethyl5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate

To a solution of ethyl 5,6-dichloronicotinate (6.28 g, 28.5 mmol) and2,2,2-trifluoroethanol (2.71 ml, 37.1 mmol) in THF (90 ml) at −73° C.was added NaHMDS (37.1 ml, 37.1 mmol). The reaction was stirred at −73°C. for 30 minutes, then at 0° C. for 5 hours. The reaction was quenchedwith 30 mL saturated NH₄Cl solution. The reaction mixture was thenpoured into 50 mL brine and phases were separated. The aqueous layer wasextracted with DCM (2×100 mL). The combined organics were dried (Na₂SO₄)and concentrated. Silica gel chromatography with 100% heptane to 30%EtOAc in heptane provided final product (7.51 g). LCMS m/z 284.1 (M+H)⁺,Rt 1.07 min.

Step 2: Preparation of(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol

To a solution of ethyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate(7.51 g, 26.5 mmol) in Et2O (200 mL) was added LiBH₄ (0.865 g, 39.7mmol), followed by drop wise addition of methanol (1.611 ml, 39.7 mmol).The reaction was refluxed at 40° C. for one hour. The reaction mixturewas then cooled to 0° C., and quenched with HCl (1M) until pH=2 foraqueous layer. The phases were separated and the aqueous layer wasextracted with DCM (3×200 mL). The organic was then dried (Na₂SO₄) andconcentrated under reduced pressure to give final crude product (6.31g). LCMS m/z 242.1 (M+H)⁺, Rt 0.77 min.

Step 3: Preparation of 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinaldehyde

To a solution of(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (4.00 g, 16.56mmol) in EtOAc (15 mL) was added manganese(IV) oxide (16.93 g, 166mmol). The reaction was heated with microwave at 120° C. for 30 minutes.The mixture was then filtered through a pad of celite, and rinsed withEtOAc. The filtrated was concentrated to give crude product (3.38 g).

Intermediate 306: (S)-1-(2,3-difluorophenyl)ethanamine

Step 1

To a oven dried round bottom flask with stir bar was added2,3-difluorobenzaldehyde (0.5 g, 3.52 mmol),(R)-2-methylpropane-2-sulfinamide (0.469 g, 3.87 mmol) and DCE (7.04mL). To this mixture was then added Copper (II) Sulfate (0.842 g, 5.28mmol). Reaction mixture heated in a preheated oil bath to 55° C. for 24hr. The reaction mixture was filtered through a celite pad washingsolids with DCE. Combined filtrate was concentrated to afford a viscousyellow oil of(R,E)-N-(2,3-difluorobenzylidene)-2-methylpropane-2-sulfinamide (0.8007g, 3.26 mmol, 93% yield). MS m/z 246.1 (M+H)+; Rt-0.91 min.

Step 2

To a solution of(R,E)-N-(2,3-difluorobenzylidene)-2-methylpropane-2-sulfinamide (0.800g, 3.26 mmol) in DCM (32.6 mL), cooled to 0° C. (water/icebath) underN2, was added 3M MeMgBr (4.35 mL, 13.05 mmol) in diethyl ether. Reactionmixture allowed to stir for 30 min at 0° C. Then gradually allowed towarm to room temperature and stirred for 30 min at room temperature.Reaction mixture was cooled to 0° C. then quenched with the slowaddition of a saturated solution of NH4Cl and diluted with EtOAc. Phasespartitioned aqueous phase extracted with EtOAc and the organic layerscombined washed with water, brine, dried with MgSO4, filtered andconcentrated to afford(R)—N—((S)-1-(2,3-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(0.7868 g, 3.01 mmol, 92% yield) as yellow solid. MS m/z 262.0 (M+H)+;Rt-0.70 min.

Step 3

To a round bottom flask containing(R)—N—((S)-1-(2,3-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(786.8 mg, 3.01 mmol) was added Dioxane (10.000 mL). To this solutionwas added HCl in dioxane 4.0M (1.505 mL, 6.02 mmol) and the solution wasallowed to stir 15 min at room temperature. The reaction mixture wasconcentrated, dissolved in Et2O 10 ml, and concentrated again. Et2O wasagain added and resulting mixture sonicated and a solid material wasfiltered and dried to afford (S)-1-(2,3-difluorophenyl)ethanamine(0.4213 g, 2.176 mmol, 72.3% yield) as a white crystalline HCl salt. 1HNMR (400 MHz, <d2o>) d ppm 1.55 (d, J=6.99 Hz, 3H) 4.71 (q, J=6.96 Hz,1H) 7.10-7.26 (m, 3H); MS m/z 158.0 (M+H)+; Rt-0.37 min.

The intermediates in Table A were prepared using a method similar tothat described for the preparation of Intermediate 306

TABLE 18a

Intermediate 307

Intermediate 308

Intermediate 309

TABLE 18b Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 18a. Intermediate: Name Analytical data 307:(S)-1-(3,4- ¹H NMR (400 MHz, <cd3od>) δ ppm difluorophenyl)ethanamine1.61 (d, J = 6.90 Hz, 3 H) 4.47 (q, J = 6.90 Hz, 1 H) 7.25-7.30 (m, 1 H)7.32-7.46 (m, 2 H) LCMS m/z 158.1.1 (M + H)⁺; Rt-0.39 min. 308:(S)-1-(2,4- ¹H NMR (400 MHz, <cd3od>) δ ppm difluorophenyl)ethanamine1.65 (d, J = 1.00 Hz, 3 H) 4.71 (q, J = 6.91 Hz, 1 H) 7.05-7.15 (m, 2 H)7.51-7.61 (m, 1 H) LCMS m/z 158.1.1 (M + H)⁺; Rt-0.37 min.

Intermediate 310: (S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethanamine

Step 1: Preparation 1-(4-bromo-3-fluorophenyl)ethanol

Methylmagnesium bromide (3M in diethylether, 6.77 mL, 20.31 mmol) wasadded dropwise over ˜15 min to a solution of4-bromo-3-fluorobenzaldehyde (3.1 g, 15.27 mmol) in THF (50 mL) underargon at a temperature of −60° C. to −50° C. The ice bath was removedand the reaction mixture was allowed to warm to room temperature andstirred ˜20 hr. The reaction mixture was slowly diluted/quenched withsaturated aqueous ammonium chloride solution (20 mL) and further dilutedwith water (10 mL). The separated aqueous layer was extracted with ethylacetate (2×40 mL). The combined organic layers were washed with brine(60 mL), dried over sodium sulfate, filtered and concentrated underreduced pressure to provide crude 1-(4-bromo-3-fluorophenyl)ethanol as apale yellow oil, which was directly used without further purification.

LCMS m/z 201.0 (M−H₂O)⁺, Rt 0.75 min.

Step 2: Preparation 1-(4-bromo-3-fluorophenyl)ethanone

To a solution of crude 1-(4-bromo-3-fluorophenyl)ethanol oil (fromStep 1) in DCM (100 mL) was added pyridinium dichromate (8.96 g, 23.82mmol). The mixture was stirred overnight at room temperature. To themixture was added celite, the reaction mixture was filtered through acelite pad and rinsed several times with DCM. The filtrate wasconcentrated under reduced pressure. The crude material was purified bycolumn chromatography [SiO₂, 40 g, heptane/ethyl acetate] providing1-(4-bromo-3-fluorophenyl)ethanone (3.08 g) as a white solid. ¹H NMR(400 Mhz, CDCl₃) δ ppm 7.72-7.58 (m, 3H), 2.59 (s, 3H).

Step 3: Preparation 1-bromo-4-(1,1-difluoroethyl)-2-fluorobenzene

To a solution of 1-(4-bromo-3-fluorophenyl)ethanone (3.08 g, 14.19 mmol)in chloroform (15 mL) was added DAST (5.62 mL, 42.6 mmol) and ethanol(0.083 mL, 1.42 mmol). The orange solution was heated at 60° C. for 24hr in a sealed container. The reaction mixture was allowed to cool to˜20° C. and to the mixture was added slowly saturated aqueous sodiumbicarbonate solution (75 mL). Stirring was continued until off-gassedceased (˜15 min). The separated aqueous layer was diluted withadditional saturated aqueous sodium bicarbonate solution (25 mL) andcarefully mixed. The basic aqueous layer was extracted with DCM (2×100mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography [SiO₂, heptane/ethyl acetate]providing 1-bromo-4-(1,1-difluoroethyl)-2-fluorobenzene (2.1 g) as aslightly cloudy colorless oil. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.73 (dd,J=7.2, 8.1 Hz, 1H), 7.40 (dd, J=2.0, 9.4 Hz, 1H), 7.29 (m, J=1.0 Hz,1H), 1.92 (t, J=18.4 Hz, 3H).

Step 4: Preparation 4-(1,1-difluoroethyl)-2-fluorobenzaldehyde

To a solution of 1-bromo-4-(1,1-difluoroethyl)-2-fluorobenzene (2.1 g,8.79 mmol) in THF (30.3 mL) was added n-butyllithium (1.6M in hexanes,5.60 mL) over ˜20 min at −78° C. The mixture was stirred for 30 min at−78° C. and DMF (1.02 mL, 13.18 mmol) was added dropwise over ˜4 min.Stirring was continued for 1 hr, the mixture was diluted/quenched with1N aqueous HCl/MeOH (2/1, 15 mL) and allowed to warm to roomtemperature. The reaction mixture was diluted further with water (50 mL)and extracted with diethylether (2×50 mL). The combined organic layerswere washed with 1N aqueous sodium hydroxide solution (50 mL) and brine(100 mL), dried over magnesium sulfate, filtered and concentrated underreduced pressure. The crude material was purified by columnchromatography [SiO₂, 40 g, heptane/ethyl acetate] providing4-(1,1-difluoroethyl)-2-fluorobenzaldehyde (699 mg) as a dark yellow,volatile oil, which was contaminated with1-bromo-4-(1,1-difluoroethyl)-2-fluorobenzene. ¹H NMR (400 Mhz, CDCl₃) δppm 10.40 (s, 1H), 7.95 (t, J=7.4 Hz, 1H), 7.39-7.47 (m, 2H), 7.35 (d,J=10.6 Hz, 1H), 1.94 (t, J=18.2 Hz, 4H) 7.73 (dd, J=7.2, 8.1 Hz, 1H).

Step 5: Preparation(R,E)-N-(4-(1,1-difluoroethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide

To a mixture of 4-(1,1-difluoroethyl)-2-fluorobenzaldehyde (693 mg, fromStep 4) and (R)-2-methylpropane-2-sulfinamide (513 mg, 4.24 mmol) in DCE(12.9 mL) was added copper(II) sulfate (882 mg, 5.52 mmol). The reactionmixture was placed in a pre-heated oil bath (55° C.) and heated for ˜2d. The mixture was allowed to cool to room temperature, filtered througha pad of celite and rinsed with DCE. The combined filtrates wereconcentrated under reduced pressure. The residue was purified by columnchromatography [SiO₂, 24 g, heptane/ethyl acetate] providing(R,E)-N-(4-(1,1-difluoroethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide(497 mg) as a yellow oil. LCMS m/z 292.1 (M+H)⁺, Rt 0.97 min.

Step 6: PreparationN—((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of(R,E)-N-(4-(1,1-difluoroethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide(497 mg, 1.706 mmol) in DCM (9.59 mL) was added methylmagnesium bromide(3M in diethylether; 1.20 mL) at 0° C. The reaction mixture was allowedto stir for 1 hr at 0° C., gradually allowed to warm to room temperatureand stirred for 1 hr at room temperature. The mixture was cooled to 0°C., additional methylmagnesium bromide (3M in diethylether; 0.5 mL) wasadded and stirring was continued for 30 min at 0° C. The reactionmixture was carefully quenched with saturated aqueous ammonium chloridesolution (6 mL) and diluted with water (20 mL). The separated aqueousphase was extracted with DCM (30 mL). The combined organic layers werewashed with brine (50 mL), concentrated under reduced pressure. Theresidue was purified by column chromatography [SiO₂, 24 g, heptane/ethylacetate] providingN—((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(349 mg) as a white solid. LCMS m/z 308.2 (M+H)⁺, Rt 0.91 min.

Step 7: Preparation(S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethanamine

ToN—((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(349 mg, 1.135 mmol) was added 4M HCl in dioxane (3.01 mL) to give apurple solution. To the mixture was added diethylether (20 mL) and themixture was stirred for 15 min at ˜10° C. The mixture was concentratedunder reduced pressure to ˜2 mL of volume and diethylether (20 mL) wasadded. The solids were filtered off, rinsed with diethylether (4×10 mL)and dried under reduced pressure providing(S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethanamine (244 mg) as anoff-white solid (HCl salt). LCMS m/z 204.1 (M+H)⁺, Rt 0.42 min.

Intermediate 311: (S)-tert-butyl 1-(3-hydroxyphenyl)ethylcarbamate

A slurry of (S)-3-(1-aminoethyl)phenol (1.188 g, 6.84 mmol) and Boc₂O(1.747 mL, 7.53 mmol) in DCM (17.10 mL) was stirred at room temperatureunder N₂ while slowly adding DIEA (1.434 mL, 8.21 mmol). The initiallyinsoluble starting materials slowly dissolve. The solution was stirredat room temperature for 16 hours and then concentrated. The oily residuewas re-dissolved in EtOAc and washed with Na₂CO₃ saturated, followed bybrine. The original aqueous layer was re-extracted with EtOAc, which wasthen washed with brine and combined with the previous EtOAc batch. Thecombined organics were dried over Na₂SO₄, filtered and concentrated to2.4 g crude clear yellowish oil which was purified by silica gel columnchromatography (EtOAc/Heptane 0 to 30%), yielding (S)-tert-butyl1-(3-hydroxyphenyl)ethylcarbamate as a clear colourless oil, whichsolidifies upon sitting (1.79 g, 7.55 mmol, 110% yield). ¹H NMR (400MHz, CDCl₃) δ 1.44 (br. s., 12H) 4.08-4.18 (m, 1H) 4.76 (br. s., 1H)6.72 (dd, J=7.46, 1.83 Hz, 1H) 6.78 (br. s., 1H) 6.88 (br. s., 1H)7.16-7.24 (m, 1H). LCMS m/z 223.0/182.0 (the parent not observed, justthe Boc fragments) (M+H)⁺, Rt 0.71 min.

Intermediate 312: (S)-tert-butyl1-(4-hydroxy-3-methylphenyl)ethylcarbamate

Made as above Intermediate 195: (S)-tert-butyl1-(4-hydroxy-3-methylphenyl)ethylcarbamate, clear colourless oil. (1.27g, 5.05 mmol, 103% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.42 (s, 9H) 1.54(s, 3H) 2.24 (s, 3H) 4.70 (br. s., 1H) 6.72 (d, J=8.22 Hz, 1H) 7.01 (d,J=9.00 Hz, 1H) 7.05 (s, 1H). LCMS m/z 252.2 (M+H)⁺, Rt 0.80 min.

Intermediate 313: (S)-1-(3-(cyclohexyloxy)phenyl)ethanamineHydrochloride

Step 1

To a solution of (S)-tert-butyl 1-(3-hydroxyphenyl)ethylcarbamate (100mg, 0.421 mmol), cyclohexanol (0.180 ml, 1.686 mmol) and PPh₃ (221 mg,0.843 mmol) in THF (2 ml), was added DEAD (0.133 ml, 0.843 mmol)dropwise, under N₂, at room temperature. The resulting yellow solutionwas stirred for 3 hours, at which point another batch of cyclohexanol(0.180 ml, 1.686 mmol), PPh₃ (221 mg, 0.843 mmol), and 10 min later DEAD(0.133 ml, 0.843 mmol), was added at room temperature. The reactionmixture was stirred for 16 hours and then concentrated. The crude clearoil was re-dissolved in DMSO and purified by reverse phase HPLC. Thecombined product fractions were desalted by addition of equal amount ofEtOAc and about 250 mg Na₂CO₃ in a separatory funnel. The phases wereseparated and the organic washed with brine, dried over MgSO₄, filteredand concentrated in vacuo to yield (S)-tert-butyl1-(3-(cyclohexyloxy)phenyl)ethylcarbamate (74.1 mg, 0.232 mmol, 55.0%yield) as a clear colourless film. LCMS m/z 305.0/264.0 (the parent notobserved, just the Boc fragments) (M+H)⁺, Rt 1.12 min.

Step 2

(S)-tert-butyl 1-(3-(cyclohexyloxy)phenyl)ethylcarbamate (74.1 mg, 0.232mmol) was dissolved in 4M HCl in dioxane (1 ml, 4.00 mmol) and theresulting mixture was allowed to sit for 1 hour, then concentrated toyield (S)-1-(3-(cyclohexyloxy)phenyl)ethanamine as an HCl salt (yieldassumed quantitative). LCMS m/z 220.1 (M+H)⁺, Rt 0.66 min.

The Intermediates in Table 19 were prepared using the method describedfor the preparation of Intermediate 313.

TABLE 19 Intermediate: Name Structure LCMS 314: (S)- 1-(3-((S)-tetrahydro- furan- 3-yloxy) phenyl) ethanamine

MS m/z 208.1 (M + H)⁺, Rt 0.41 min. 315: (S)- 1-(3- isobutoxy- phenyl)ethanamine

MS m/z 194.1 (M + H)⁺, Rt 0.61 min. 316: (S)- 1-(4- isobutoxy- 3-methyl-phenyl) ethanamine

MS m/z 191.1 (M + H)⁺, Rt 0.70 min. 317: (S)-1- (2-fluoro-4- isobutoxy-phenyl) ethanamine

MS m/z 195.2 (M + H)⁺, Rt 0.64 min. 318: (S)- 1-(4- (cyclopropyl-methoxy) phenyl) ethanamine

MS m/z 175.1 (M + H)⁺, Rt 0.53 min.

Intermediate 319: (S)-1-(3-phenoxyphenyl)ethanamine

Into a 20 ml microwave vial was weighted 1-(pyridin-2-yl)propan-2-oneligand (90 mg, 0.665 mmol), phenol (407 mg, 4.32 mmol), CuBr (47.7 mg,0.332 mmol) and Cs₂CO₃ (2166 mg, 6.65 mmol). To the mixture was addedDMSO (5 ml) and (S)-1-(3-bromophenyl)ethanamine (0.5 ml, 3.32 mmol). Thetube was flushed with N₂, capped, and the black mixture heated in theoil bath at 90° C. for 18 hours. The heterogenous mixture was dilutedwith EtOAc and filtered through a glass-fritted funnel, eluting withEtOAc and another 5 mls of DMSO. The volatiles were then removed invacuo and the crude brown liquid was filtered through lum PTFE filterand purified by reverse phase HPLC. The combined product fractions weredesalted by addition of equal amount of EtOAc and about 250 mg Na₂CO₃ ina separatory funnel. The phases were separated and the organic washedwith brine, dried over MgSO₄, filtered and concentrated in vacuo toyield (S)-1-(3-phenoxyphenyl)ethanamine (361.5 mg, 1.678 mmol, 50.5%yield) as an amber oil. LCMS m/z 214.1 (M+H)⁺, Rt 0.61 min.

Intermediate 320: (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine

Step 1

To a cloudy solution of 4-(trifluoromethoxy)benzaldehyde (5 g, 26.3mmol) and (R)-2-methylpropane-2-sulfinamide (3.51 g, 28.9 mmol) in DCE(52 mL), under N₂, was added copper (II) sulfate (6.30 g, 39.4 mmol),and the resulting mixture heated in a preheated oil bath at 55° C. for22 hours. The reaction mixture was filtered through a pad of celite,eluting with DCM. The filtrate was concentrated to afford a viscousyellow oil of(R,E)-2-methyl-N-(4-(trifluoromethoxy)benzylidene)propane-2-sulfinamide(7.9 g, 26.9 mmol, 102% yield). Material was taken onto next stepwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.27 (s, 9H)7.32 (d, J=8.07 Hz, 2H) 7.91 (d, J=8.75 Hz, 2H) 8.59 (s, 1H). LCMS m/z294.1 (M+H)⁺, Rt 1.01 min.

Step 2

To a solution of(R,E)-2-methyl-N-(4-(trifluoromethoxy)benzylidene)propane-2-sulfinamide(7.7 g, 26.3 mmol) in CH₂Cl₂ (150 mL), cooled to 0° C. (water/ice bath),under nitrogen, was added 3M methyl magnesium bromide (35 mL, 105 mmol)in Et₂O. The reaction mixture was stirred at 0° C. for 30 min, thenallowed to warm up to room temperature and stirred additional 4 hrs. Thereaction mixture was cooled again to 0° C. and quenched with the slowaddition of a saturated NH₄Cl solution. The by-phasic mixture wasdiluted with DCM and Water and the aqueous extracted with DCM two times.The organic phases were combined, washed with brine, dried (Na₂SO₄),filtered and concentrated to 11.5 g crude white solid. Silica gel columnchromatography (EtOAc/Heptane 0 to 30%) afforded(R)-2-methyl-N—((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide(5.08 g, 16.2 mmol, 62% yield) as a white crystalline solid. ¹H NMR (400MHz, CDCl₃) δ 1.21 (s, 9H) 1.53 (d, J=6.70 Hz, 3H) 3.31 (d, J=2.74 Hz,1H) 4.59 (qd, J=6.67, 3.37 Hz, 1H) 7.18 (d, J=8.02 Hz, 2H) 7.36 (d,J=8.66 Hz, 2H). LCMS m/z 310.2 (M+H)⁺, Rt 0.90 min.

Step 3

(R)-2-methyl-N—((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide(5.08 g, 16.4 mmol) was dissolved by swirling in 4M HCl in dioxane (16.4ml, 65.6 mmol), at room temperature. The solution was allowed to sit for1 hr with occasional swirling. To the clear solution was added 45 mlether and the resulting cloudy solution sonicated for 1 min, upon whichtime the white solid product precipitates out. The solid was filteredthrough a Buchner funnel, washed 5 times with ˜20 ml ether and allowedto air dry. Obtained (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (3.2g, 13.2 mmol, 80% yield), ¹H NMR (400 MHz, CD₃OD) δ 1.64 (d, J=6.90 Hz,3H) 4.52 (q, J=6.88 Hz, 1H) 7.38 (d, J=8.02 Hz, 2H) 7.57 (d, J=8.71 Hz,2H). LCMS m/z 206.1 (M+H)⁺, Rt 0.52 min.

The Intermediates in Table 20 were prepared using the method describedfor the preparation of Intermediate 320.

TABLE 20 Intermediate: Name Structure ¹H-NMR (400 MHz, CD₃OD), LCMS 321:(S)-1-(2-fluoro-4- (trifluoromethoxy) phenyl) ethanamine

δ ppm 1.66 (d, J = 6.94 Hz, 3 H) 4.75 (q, J = 6.94 Hz, 1 H) 7.23-7.31(m, 2 H) 7.60- 7.68 (m, 1 H). MS m/z 224.1 (M + H)⁺, Rt 0.54 min. 322:(S)-1-(4- (difluoromethoxy) phenyl) ethanamine

δ ppm 1.63 (d, J = 6.90 Hz, 3 H) 4.48 (q, J = 6.88 Hz, 1 H) 6.63-7.10(m, 1 H) 7.24 (d, J = 8.71 Hz, 2 H) 7.50 (d, J = 8.66 Hz, 2 H). MS m/z171.1 (M + H)⁺, Rt 0.43 min. 323: (S)-1-(3-fluoro-4- (trifluoromethoxy)phenyl) ethanamine

δ ppm 1.64 (d, J = 6.90 Hz, 3 H) 4.54 (q, J = 6.88 Hz, 1 H) 7.39 (dt, J= 8.52, 1.56 Hz, 1 H) 7.46-7.59 (m 2 H). MS m/z 224.1 (M + H)⁺, Rt 0.55min. 324: (S)-1-(4- (difluoromethoxy)-3- fluorophenyl) ethanamine

δ ppm 1.62 (d, J = 6.90 Hz, 3 H) 4.49 (q, J = 6.83 Hz, 1 H) 6.67-7.10(m, 1 H) 7.27- 7.33 (m, 1 H) 7.35-7.44 (m, 2 H). MS m/z 206.1 (M + H)⁺,Rt 0.46 min. 325: (S)-1-(4- (difluoromethoxy)-2- fluorophenyl)ethanamine

δ ppm 1.65 (d, J = 6.94 Hz, 3 H) 4.71 (q, J = 6.94 Hz, 1 H) 6.71-6.97(m, 1 H) 7.05- 7.14 (m, 2 H) 7.55 (t, J = 8.68 Hz, 1 H). MS m/z 206.1(M + H)⁺, Rt 0.46 min. 326: (S)-1-(3- (trifluoromethoxy) phenyl)ethanamine

δ ppm 1.63 (d, J = 6.90 Hz, 3 H) 4.53 (q, J = 6.86 Hz, 1 H) 7.35 (ddt, J= 8.21, 2.27, 1.09, 1.09 Hz, 1 H) 7.41 (s, 1 H) 7.47 (d, J = 7.82 Hz, 1H) 7.54-7.61 (m, 1 H). MS m/z 206.1 (M + H)⁺, Rt 0.51 min. 327:(S)-1-(3- (difluoromethoxy) phenyl) ethanamine

δ ppm 1.63 (d, J = 6.90 Hz, 3 H) 4.49 (q, J = 6.88 Hz, 1 H) 6.64-7.08 (m1 H) 7.21 (dd, J = 8.19, 1.83 Hz, 1 H) 7.26 (t, J = 2.03 Hz, 1 H) 7.33(d, J = 7.78 Hz, 1 H) 7.45-7.53 (m, 1 H). MS m/z 188.1 (M + H)⁺, Rt 0.43min.

Intermediate 328(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-(((S)-1-(piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

To a Parshaker flask were added benzyl4-((S)-1-((4-((R)-4-((S)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-5-fluoropyrimidin-2-yl)amino)ethyl)piperidine-1-carboxylate(850 mg, 1.56 mmole) and 20% Pd(OH)₂ in actived carbon (880 mg, 1.25mmole), then was added MeOH (100 mL) under nitrogen gas. The reactionmixture was shaked under 50 psi hydrogen overnight. The reaction mixturewas filtered through a celite. The celite cake was washed with MeOH andthe filtrate was concentrate in vacuo. The resulting crude product waspurified by flash column chromatography (basic alumina, 40 g) eluting w/0-20% MeOH/DCM to afford the title product as a white solid (230 mg). ¹HNMR (400 MHz, CD₂Cl₂) δ 8.18 (d, J=2.87 Hz, 1H), 5.15 (br s, 1H),4.71-4.63 (m, 1H), 4.56-4.47 (m, 1H), 4.47-4.34 (m, 2H), 4.25-4.14 (m,1H), 3.96-3.82 (m, 1H), 3.16 (d, J=12.34 Hz, 2H), 2.67-2.54 (m, 2H),1.85-1.66 (m, 2H), 1.64-1.52 (m, 1H), 1.40-1.26 (m, 2H), 1.20 (d, J=6.60Hz, 3H), 1.18 (s, 9H), 1.10 (d, J=6.46 Hz, 3H). HRMS(C) tR=2.36 min; MSm/z 410.2571 (M+H)+

Intermediate 329(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(4-chloro-3-(trifluoromethoxy)phenyl)piperidin-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

A cloudy solution of(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-(((S)-1-(piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (32 mg, 0.078 mmol),4-bromo-1-chloro-2-(trifluoromethyoxy)benzene (26 mg, 0.094 mmol),Pd(OAc)₂ (2 mg, 8 umol), BINAP (5 mg, 8 umol), and Cs₂CO₃ (51 mg, 0.156mmol) in 6 mL toluene was heated at 90° C. for 3 days. The mixture wascooled to room temperature, and filtered through Celite. The celite cakewas rinsed with 5 mL EtOAc. The filtrate was poured into 5 mL water.Organic layer was separated, and the aqueous was further extracted withEtOAc (5 mL). The organic extracts were combined and concentrated byrotary evaporation. The crude was dissolved in a mixture of MeOH (1 mL)and DMSO (1 mL) and purified by reverse phase HPLC. Selected fractionswere collected and concentrated by rotary evaporation to afford thetitle product as a colorless oil (34 mg). (400 MHz, CD₂Cl₂) δ 8.19 (d,J=2.95 Hz, 1H), 7.31 (d, J=8.85 Hz, 1H), 6.87-6.80 (m, 2H), 5.05 (br s,1H), 4.73-4.63 (m, 1H), 4.56-4.44 (m, 2H), 4.25-4.13 (m, 1H), 4.01-3.88(m, 1H), 3.79-3.69 (m, 2H), 2.82-2.69 (m, 2H), 2.00-1.79 (m, 2H),1.68-1.56 (m, 1H), 1.54-1.36 (m, 2H), 1.23 (d, J=6.87 Hz, 3H), 1.15 (s,9H), 1.09 (d, J=6.44 Hz, 3H), HRMS(C) tR=5.61 min; MS m/z 604.2328(M+H)+

The intermediates in Table 21 were prepared with procedures similar tothose used to prepare Intermediate 301

TABLE 21 Intermediate: Name Structure LCMS 330:(R)-N-((S)-1-(5-chloro-6- (1,1-difluoroethyl)pyridin-3-yl)ethyl)-2-methylpropane-2- sulfinamide

MS m/z 325.2 (M + H)⁺, Rt 0.85 min. 331: (R)-N-((S)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3- yl)ethyl)-2-methylpropane-2-sulfinamide

MS m/z 359.1 (M + H)⁺, Rt 0.95 min.

The intermediates in Table 22 were prepared with procedures similar tothose used to prepare Intermediate 302

TABLE 22 Intermediate: Name Structure LCMS 332: (S)-1-(5-chloro-6-(1,1-difluoroethyl)pyridin-3- yl)ethanamine

MS m/z 221.1 (M + H)⁺, Rt 0.50 min. 333: (S)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3- yl)ethanamine

MS m/z 255.1 (M + H)⁺, Rt 0.62 min.

The intermediates in Table 23a were prepared using a method similar tothat described for the preparation of Intermediate 306

TABLE 23a

Intermediate 334

Intermediate 335

Intermediate 336

Intermediate 337

Intermediate 338

Intermediate 339

Intermediate 340

Intermediate 341

TABLE 23b Chemical name and analytical data for each intermediate listedin Table 23a. Intermediate: Name Analytical data 334:(S)-1-(4-bromo-2,5- LCMS m/z (M + H)⁺ 236.0, difluorophenyl)ethanamineRT 0.5 min. 335: (S)-1-(4-bromo-2,3- LCMS m/z (M + H)⁺ 238.1,difluorophenyl)ethanamine RT 0.55 min. 336: (S)-1-(4-bromo-2- LCMS m/z(M + H)⁺ 218.0, 220.1, fluorophenyl)ethanamine RT 0.47 min. 337:(S)-1-(4-chloro-2- LCMS m/z (M + H)⁺ 174.2, fluorophenyl)ethanamine RT0.47 min. 338: (S)-1-(4-bromo-3- LCMS m/z (M + H)⁺ 218.1, 220.1,fluorophenyl)ethanamine RT 0.52 min. 339: (S)-1-(3,4- LCMS m/z (M + H)⁺190.0, dichlorophenyl)ethanamine RT 0.57 min. 340: (S)-1-(6-chloro-5-LCMS m/z (M + H)⁺ 175.2, fluoropyridin-3-yl)ethanamine RT 0.37 min. 341:(S)-1-(5,6- LCMS m/z (M + H)⁺ 191.1, dichloropyridin-3-yl)ethanamine RT0.42 min.

Intermediate 342:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

A solution of(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(112 mg, 0.40 mmol), (S)-1-phenylethanamine (58 mg, 0.48 mmol, 1.2equiv), and DIPEA (153 mg, 1.2 mmol, 3.0 equiv) in DMSO (4.0 mL) washeated at 100° C. for 90 min. The reaction mixture was

poured into 5 ml of water, extracted with EA (2×10 ml), the solvent wasremoved to yield the crude product. Silica gel column chromatography(ethyl acetate in heptane 10 to 50%) provided the pure product (142 mg,white solid) in a 93% yield. HRMS m/z 385.2231 (M+H)⁺, RT=3.35 min.

The Following Intermediates were prepared using a method similar to thatdescribed for the preparation of Intermediate 342 or Example 3

Intermediate 343:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(2,3-dihydro-1H-inden-5-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(B) tR=3.54 min; m/z 492.2485

Intermediate 344(4R)-3-(2-((1-(3-(4-bromo-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one

HRMS(C) tR=1.76 min; MS m/z 561.43

Intermediate 345(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.94 min; m/z 480.2485

Intermediate 346(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.78 min; m/z 498.2391

Intermediate 347(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-phenethyl-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.71 min; m/z 480.2485

Intermediate 348(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(isoquinolin-8-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(B) tR=2.77 min; m/z 504.2337 (M+H)

Intermediate 349(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.96 min; m/z 554.1656

Intermediate 350(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(B) tR=3.13 min; m/z 518.2089

Intermediate 351(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.97 min; m/z 536.1995

Intermediate 352(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.91 min; m/z 520.2046

Intermediate 353(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.87 min; m/z 520.2046

Intermediate 354(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(2-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.76 min; m/z 536.1995

Intermediate 355(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.76 min; m/z 550.2151

Intermediate 356(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(B) tR=3.38 min; m/z 532.1882

Intermediate 357(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(3,4-dimethylphenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.63 min; m/z 480.2485

Intermediate 358(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

HRMS(B) tR=1.65 min; MS m/z 518.1 (M+H)

Intermediate 359(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(B) tR=1.59 min; MS m/z 486.2

Intermediate 360(4R)-3-(2-((1-(3-(4-bromo-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one

HRMS(C) tR=1.76 min; MS m/z 561.43

Intermediate 361(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.94 min; m/z 480.2485

Intermediate 362(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-((1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.96 min; m/z 512.2548

Intermediate 363(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.78 min; m/z 498.2391

Intermediate 364(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-phenethyl-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.71 min; m/z 480.2485

Intermediate 365(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(isoquinolin-8-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(B) tR=2.77 min; m/z 504.2337 (M+H)

Intermediate 366(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.96 min; m/z 554.1656

Intermediate 367(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(B) tR=3.13 min; m/z 518.2089

Intermediate 368(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.97 min; m/z 536.1995

Intermediate 369(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.91 min; m/z 520.2046

Intermediate 370(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.87 min; m/z 520.2046

Intermediate 371(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(2-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.76 min; m/z 536.1995

Intermediate 372(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(3-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.76 min; m/z 550.2151

Intermediate 373(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(B) tR=3.38 min; m/z 532.1882

Intermediate 374(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(3,4-dimethylphenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(C) tR=1.63 min; m/z 480.2485

Intermediate 375(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

HRMS(B) tR=1.65 min; MS m/z 518.1 (M+H)

Intermediate 376(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(4-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

HRMS(B) tR=1.59 min; MS m/z 486.2

Intermediate 377:(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-((1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

Anal. RP-HPLC tR=1.69 min; MS m/z 611.1 (M+H)+.

Intermediate 378 benzyl4-((S)-1-((4-((R)-4-((S)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-5-fluoropyrimidin-2-yl)amino)ethyl)piperidine-1-carboxylate

¹H NMR (400 MHz, CD₂Cl₂) δ 8.18 (s, 1H), 7.41-7.30 (m, 5H), 5.15 (s,2H), 5.03 (br s, 1H), 4.71-4.64 (m, 1H), 4.54-4.45 (m, 2H), 4.30-4.12(m, 3H), 3.99-3.86 (m, 1H), 2.77 (br s, 2H), 1.87-1.57 (m, 3H),1.36-1.24 (m, 2H), 1.20 (d, J=6.44 Hz, 3H), 1.16 (s, 9H), 1.09 (d,J=5.91 Hz, 3H). HRMS(C) tR=4.46 min; MS m/z 544.2964 (M+H)+

Intermediate 379:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl3) δ 8.72 (d, J=2.3 Hz, 1H), 8.21 (d, J=5.7 Hz,1H), 7.79 (dd, J=8.1, 2.4 Hz, 1H), 7.47 (d, J=5.8 Hz, 1H), 7.39-7.28 (m,3H), 7.13-7.07 (m, 1H), 5.28 (p, J=6.9 Hz, 1H), 4.75 (dt, J=8.1, 3.5 Hz,1H), 4.62 (dd, J=9.4, 3.1 Hz, 1H), 4.49-4.40 (m, 1H), 4.34 (t, J=9.0 Hz,1H), 2.35 (d, J=1.9 Hz, 3H), 1.60 (d, J=6.7 Hz, 3H), 1.25 (s, 12H), 1.01(d, J=6.5 Hz, 3H); MS m/z 492.6 (M−H).

Intermediate 380:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.86 min; MS m/z 528.5 (M−H)+.

Intermediate 381:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(6-(4-fluoro-3-methylphenyl)pyridin-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.69 min; MS m/z 494.0 (M+H)+.

Intermediate 382:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.74 min; MS m/z 530.0 (M+H)+.

Intermediate 383:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl3) δ 8.86 (d, J=2.3 Hz, 1H), 8.83 (d, J=5.1 Hz,1H), 8.20 (d, J=5.7 Hz, 1H), 7.93 (dd, J=8.1, 2.4 Hz, 1H), 7.87 (s, 1H),7.69 (dd, J=5.2, 1.7 Hz, 1H), 7.48 (d, J=5.8 Hz, 1H), 7.45 (d, J=8.1 Hz,1H), 6.37-5.79 (m, 1H), 5.33 (p, J=6.9 Hz, 1H), 4.74 (ddd, J=8.2, 4.6,3.0 Hz, 1H), 4.62 (dd, J=9.3, 3.0 Hz, 1H), 4.43 (qd, J=6.4, 4.2 Hz, 1H),4.34 (t, J=9.0 Hz, 1H), 1.67 (br s, 1H), 1.62 (d, J=6.8 Hz, 3H), 1.26(s, 9H), 1.02 (d, J=6.4 Hz, 3H); MS m/z 531.3 (M+H).

Intermediate 384:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(6′-(trifluoromethyl)-[2,3′-bipyridin]-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.51 min; MS m/z 531.1 (M+H).

Intermediate 385:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(6′-(trifluoromethyl)-[3,3′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.51 min; MS m/z 531.3 (M+H).

Intermediate 386:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(6-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.59 min; MS m/z 531.2 (M+H).

Intermediate 387:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.60 min; MS m/z 545.2 (M+H).

Intermediate 388:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.65 min; MS m/z 545.2 (M+H).

Intermediate 389:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-fluoro-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.65 min; MS m/z 549.2 (M+H).

Intermediate 390:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-methyl-2-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.65 min; MS m/z 545.6 (M+H).

Intermediate 391:(R)-4-((S)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.63 min; MS m/z 543.5 (M+H).

Intermediate 392:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=0.94 min; MS m/z 486.0 (M−H).

Intermediate 393:(R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(4-((4,4-difluoropiperidin-1-yl)methyl)-3-fluorophenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.81 min; MS m/z 534.5 (M−H).

Intermediate 394:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.74 min; MS m/z 531.0 (M+H).

Intermediate 395:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.71 min; MS m/z 495.0 (M+H).

Intermediate 396:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(4-(2,4-dichlorophenyl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

LCMS tR=1.84 min; MS m/z 536.0 (M+H).

Intermediate 397:(R)-3-(2-(((S)-1-(4-(4-bromophenyl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one

LCMS tR=1.77 min; MS m/z 548.0 (M+H).

Intermediate 398:4-(2-((S)-1-((4-((R)-4-((R)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)thiazol-4-yl)benzonitrile

LCMS tR=1.55 min; MS m/z 493.1 (M+H).

Intermediate 399:(R)-3-(2-(((S)-1-(5-bromopyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl3) δ 8.61 (d, J=2.2 Hz, 1H), 8.15 (d, J=6.0 Hz,1H), 7.78 (dd, J=8.3, 2.3 Hz, 1H), 7.50 (d, J=5.9 Hz, 1H), 7.21 (d,J=8.3 Hz, 1H), 5.22 (p, J=6.9 Hz, 1H), 4.72 (ddd, J=8.3, 4.7, 3.0 Hz,1H), 4.62 (dd, J=9.3, 3.0 Hz, 1H), 4.41-4.31 (m, 2H), 1.56 (d, J=6.8 Hz,3H), 1.21 (s, 9H), 1.00 (d, J=6.4 Hz, 3H). MS m/z 466.2 (M+H).

Intermediate 400:(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-((1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

Anal. RP-HPLC tR=1.54, 1.56 min (Column=Acquity BEH C18 1.7 μm 2.1×50mm. Column Temperature=50° C. Eluents=A: Water (3.75 mM Ammoniumformate, 2% ACN); B: ACN (3.75 mM Ammonium formate, 5% Water). FlowRate=1 mL/min. Gradient=2% to 98% B in 1.70 min.; MS m/z 549.3 (M+H)+.

Intermediate 401:(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

Anal. RP-HPLC tR=1.69 min; MS m/z 549.4 (M+H)+.

Intermediate 402:(R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)-6-(difluoromethyl)pyrimidin-4-yl)oxazolidin-2-one

A solution of(R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylsulfonyl)pyrimidin-4-yl)oxazolidin-2-one(0.146 g, 0.371 mmol),(S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine (91 mg, 0.41mmol, 1.1 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.097 mL, 0.56mmol, 1.5 equiv) in DMSO (2.0 mL) was heated at 85° C. for 18 h. Thereaction was cooled to room temperature and diluted with DCM (20 mL) andwater (20 mL). The layers were separated and the aqueous layer wasextracted with DCM (20 mL). The combined organic layers were washed withsaturated aqueous NaCl (10 mL), dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/Heptane 20% to60%) provided(R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)-6-(difluoromethyl)pyrimidin-4-yl)oxazolidin-2-oneas a yellow oily solid in 37% yield. MS m/z 537.2 (M+H)⁺; Rt-1.22 min.

Intermediate 403:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

A solution of(R)-4-((R)-1-tert-butoxyethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one(70 mg, 0.209 mmol), (S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethanamine(60 mg, 0.23 mmol, 1.1 equiv), and N-ethyl-N-isopropylpropan-2-amine(0.091 mL, 0.52 mmol, 2.5 equiv) in DMSO (1.0 mL) was heated at 85-110°C. for 3-5 h. The reaction was cooled to room temperature and dilutedwith ethyl acetate (30 mL) and dilute aqueous sodium chloride (30 mL).The layers were separated and the organic layer was dried over Na₂SO₄,filtered and concentrated to give crude(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one,which was used without further purification. MS m/z 520.2 (M+H)⁺;Rt-1.31 min.

The intermediates in Table 24a were prepared using a method similar tothat described for the preparation of Intermediate 403.

TABLE 24a

Intermediate 405

Intermediate 406

Intermediate 407

Intermediate 408

Intermediate 409

Intermediate 410

Intermediate 411

Intermediate 412

Intermediate 413

Intermediate 414

Intermediate 415

Intermediate 416

Intermediate 417

Intermediate 418

Intermediate 419

Intermediate 420

Intermediate 421

Intermediate 422

Intermediate 423

Intermediate 424

Intermediate 425

Intermediate 426

Intermediate 427

Intermediate 428

Intermediate 429

Intermediate 430

Intermediate 431

Intermediate 432

Intermediate 433

Intermediate 434

Intermediate 435

Intermediate 436

Intermediate 437

Intermediate 438

Intermediate 439

Intermediate 440

Intermediate 441

Intermediate 442

Intermediate 443

Intermediate 444

Intermediate 445

Intermediate 446

Intermediate 447

Intermediate 448

Intermediate 449

Intermediate 450

Intermediate 451

Intermediate 452

Intermediate 453

Intermediate 454

Intermediate 455

Intermediate 456

Intermediate 457

Intermediate 458

Intermediate 459

Intermediate 460

Intermediate 461

Intermediate 462

Intermediate 463

Intermediate 464

Intermediate 465

Intermediate 466

Intermediate 467

Intermediate 468

Intermediate 469

Intermediate 470

TABLE 24b Chemical name and analytical data for each intermediate listedin Table 24a. Intermediate: Name Analytical data 405:(R)-4-((R)-1-tert-butoxyethyl)-3-(6-chloro-2- MS m/z 521.1 (M + H)⁺;Rt-1.29 min ((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one 406:(R)-4-((R)-1-tert-butoxyethyl)-3-(6-chloro-2- MS m/z 505.3 (M + H)⁺;Rt-1.29 min ((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethylamino)pyrimidin-4- yl)oxazolidin-2-one 407:(R)-4-((R)-1-tert-butoxyethyl)-3-(6-chloro-2- MS m/z 517.2 (M + H)⁺;Rt-1.13 min ((S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2- one 408:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 535.2 (M + H)⁺;Rt-1.14 min (((S)-1-(2,5-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2- one 409:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 486.3 (M + H)⁺;Rt-1.25 min (((S)-1-(5-phenylisoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 410:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 537.2 (M + H)⁺;Rt-1.33 min (((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 411:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 520.2 (M + H)⁺;Rt-1.16 min (4-chlorophenyl)thiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one 412:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5- MS m/z 504.2 (M + H)⁺;Rt-1.16 min (4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one 413:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 537.2 (M + H)⁺;Rt-1.28 min (((S)-1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 414:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 519.3 (M + H)⁺;Rt-1.30 min (((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 415:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 503.4 (M + H)⁺;Rt-1.11 min (4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one 416:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5- MS m/z 518.2 (M + H)⁺;Rt-1.18 min (4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-6-(fluoromethyl)pyrimidin-4-yl)oxazolidin-2-one 417:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 534.2 (M + H)⁺;Rt-1.21 min (4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-(fluoromethyl)pyrimidin-4-yl)oxazolidin-2-one 418:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 502.2 (M + H)⁺;Rt-0.99 min (4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 419:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 485.4 (M + H)⁺;Rt-0.93 min (4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 420:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 520.2 (M + H)⁺;Rt-1.30 min (((S)-1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 421:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3- MS m/z 504.3 (M + H)⁺;Rt-1.13 min (4-chlorophenyl)isoxazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one 422:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 504.3 (M + H)⁺;Rt-1.22 min (((S)-1-(5-(4-fluorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 423:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 509.4 (M + H)⁺;Rt-0.80 min (((S)-1-(5-(morpholinomethyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 424:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 509.4 (M + H)⁺;Rt-0.83 min (((R)-1-(5-(morpholinomethyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 425:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 499.3 (M + H)⁺;Rt-0.98 min (4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-6-methylpyrimidin-4-yl)oxazolidin-2-one 426:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 503.2 (M + H)⁺;Rt-1.19 min (((S)-1-(2-(pyridin-2-yl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 427:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 503.3 (M + H)⁺;Rt-0.92 min (((S)-1-(2-(pyridin-3-yl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 428:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 503.3 (M + H)⁺;Rt-0.89 min (((S)-1-(2-(pyridin-4-yl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 429:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5- MS m/z 500.4 (M + H)⁺;Rt-1.02 min (4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-6-methylpyrimidin-4-yl)oxazolidin-2-one 430:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 516.3 (M + H)⁺;Rt-1.04 min (4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-methylpyrimidin-4-yl)oxazolidin-2-one 431:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 499.3 (M + H)⁺;Rt-0.76 min (4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)-6-methylpyrimidin-4-yl)oxazolidin-2-one 432:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(3- MS m/z 501.3 (M + H)⁺;Rt-1.04 min (4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)-6-methylpyrimidin-4-yl)oxazolidin-2-one 433:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 499.3 (M + H)⁺;Rt-1.02 min (4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)amino)-6-methylpyrimidin-4-yl)oxazolidin-2-one 434:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 500.2 (M + H)⁺;Rt-0.88 min (4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)amino)-6-methylpyrimidin-4-yl)oxazolidin-2-one 435:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2- MS m/z 520.2 (M + H)⁺;Rt-1.14 min (((S)-1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 436:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 486.3 (M + H)⁺;Rt-0.87 min (4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 437:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(4- MS m/z 481.4 (M + H)⁺;Rt-0.94 min (1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)-6-methylpyrimidin-4-yl)oxazolidin-2-one 438:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 533.4 (M + H)⁺;Rt-0.96 min (2,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)amino)-6-methylpyrimidin-4-yl)oxazolidin-2-one 439:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-methyl-2- MS m/z 497.3 (M + H)⁺;Rt-0.63 min (((S)-1-(2-(6-methylpyridin-3-yl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 440:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 537.3 (M + H)⁺;Rt-0.95 min (6-(trifluoromethyl)pyridin-3-yl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 441:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 537.3 (M + H)⁺;Rt-0.80 min (2-(trifluoromethyl)pyridin-4-yl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 442: methyl6-((R)-4-((R)-1-(tert-butoxy)ethyl)-2- MS m/z 560.3 (M + H)⁺; Rt-1.20min oxooxazolidin-3-yl)-2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidine-4- carboxylate 443:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1- MS m/z 499.2 (M + H)⁺;Rt-0.77 min (4-chlorophenyl)-2-methyl-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 444:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 518.3 (M + H)⁺;Rt-0.89 min (4-(difluoromethyl)phenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 445:(R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-(4- MS m/z 499.2 (M + H)⁺;Rt-1.27 min. chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)-6-(trifluoromethyl)pyrimidin-4-yl)oxazolidin-2-one 446:(R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(2- MS m/z 471.3 (M + H)⁺;Rt-1.01 min fluoro-4-(trifluoromethyl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one 447:(R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(4-(1- MS m/z 487.3 (M + H)⁺;Rt-1.02 min ethoxycyclopropyl)-2-fluorophenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one 448:4-((S)-1-(4-((R)-4-((R)-1-tert-butoxyethyl)-2- MS m/z 530.3 (M + H)⁺;Rt-0.91 min oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)-2-chloro-N-cyclopentylbenzamide 449:1-(4-((S)-1-(4-((R)-4-((R)-1-tert-butoxyethyl)-2- MS m/z 468.3 (M + H)⁺;Rt-0.91 min oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)-3-fluorophenyl)cyclopropanecarbonitrile 450:(R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(2- MS m/z 483.3 (M + H)⁺;Rt-0.86 min fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one 451:(R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(4-(1- MS m/z 465.3 (M + H)⁺;Rt-0.83 min methyl-1H-pyrazol-4-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one 452:(R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(2- MS m/z 469.3 (M + H)⁺;Rt-0.80 min fluoro-4-(1H-pyrazol-4-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one 453:(R)-4-((R)-1-tert-butoxyethyl)-3-(5-fluoro-2- MS m/z 489.3 (M + H)⁺;Rt-1.15 min ((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one 454:(R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(2- MS m/z 457.4 (M + H)⁺;Rt-1.06 min fluoro-4-(1-methylcyclopropyl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one 455:(R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(2- MS m/z 445.3 (M + H)⁺;Rt-1.05 min fluoro-4-isopropylphenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one 456: (R)-4-((R)-1-tert-butoxyethyl)-3-(5-fluoro-2-MS m/z 501.3 (M + H)⁺; Rt-0.98 min((S)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2- one 457:(R)-4-((R)-1-tert-butoxyethyl)-3-(5-fluoro-2- MS m/z 475.3 (M + H)⁺;Rt-1.20 min ((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one 458:(R)-4-((R)-1-tert-butoxyethyl)-3-(5-fluoro-2- MS m/z 487.2 (M + H)⁺;Rt-0.90 min ((S)-1-(2-fluoro-4-(1H-pyrazol-4-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one 459:(R)-4-((R)-1-tert-butoxyethyl)-3-(5-fluoro-2- MS m/z 463.3 (M + H)⁺;Rt-1.20 min ((S)-1-(2-fluoro-4-isopropylphenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one 460:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2- MS m/z 461.3 (M + H)⁺;Rt-1.14 min (((S)-1-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2- one 461:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 519.3 (M + H)⁺;Rt-0.98 min (2,5-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-5-fluoropyrimidin-4- yl)oxazolidin-2-one 462:(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2- MS m/z 502.3 (M + H)⁺;Rt-0.95 min (4-chlorophenyl)thiazol-5-yl)ethyl)amino) pyrimidin-4-yl)oxazolidin-2-one 463:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 457.4 (M + H)⁺; Rt1.04 min (4-isobutoxyphenyl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-one464: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2- MS m/z 451.3 (M +H)⁺; Rt 1.03 min (((S)-1-(2-fluoro-4-methoxyphenyl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-one 465:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 421.2 (M + H)⁺; Rt= 0.91 min (2,3-difluorophenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 466: (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-MS m/z 439.2 (M + H)⁺; Rt = 1.05 min;(2,3-difluorophenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one 467:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 439.2 (M + H)⁺; Rt= 1.03 min; (3,4-difluorophenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one 468:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 439.3 (M + H)⁺; Rt= 1.04 min; (2,4-difluorophenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one 469:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1- MS m/z 439.2 (M + H)⁺; Rt= 1.04 min; (3,5-difluorophenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one 470:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5-chloro-2- MS m/z 565.4 (M + H)⁺;Rt = 0.98 min; (((S)-1-(5-(2-(trifluoromethyl)pyridin-4-yl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

Intermediate 473:(2R,3R)-3-(tert-butoxy)-2-((6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)amino)butan-1-ol

A solution of(S)-4,6-difluoro-N-(1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)pyrimidin-2-amine(80 mg, 0.25 mmol), (2R,3R)-2-amino-3-(tert-butoxy)butan-1-ol (55 mg,0.28 mmol, 1.1 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.11 mL,0.63 mmol, 2.5 equiv) in DMSO (1.3 mL) was heated at 85° C. for 16hours. The reaction was cooled to room temperature and diluted withethyl acetate (30 mL) and dilute aqueous sodium chloride (30 mL). Thelayers were separated and the aqueous layer was extracted with ethylacetate (20 mL). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated. Silica gel column chromatography(EtOAc/Heptane) provided(2R,3R)-3-(tert-butoxy)-2-((6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)amino)butan-1-ol(0.058 g, white solid) in 50% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.79 (s,1H), 7.66 (s, 1H), 7.61 (m, 2H), 7.13 (t, J=8.6 Hz, 2H), 5.35 (s, 1H),5.30-5.14 (m, 2H), 5.04 (m, 1H), 3.94 (m, 1H), 3.77-3.65 (m, 2H), 1.57(d, J=6.9 Hz, 3H), 1.21 (s, 9H), 1.15 (d, J=6.0 Hz, 3H). MS m/z 461.3(M+H)⁺; Rt-0.88 min.

Intermediate 474(2R,3R)-3-(tert-butoxy)-2-((2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-6-fluoropyrimidin-4-yl)amino)butan-1-ol

(2R,3R)-3-(tert-butoxy)-2-((2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-6-fluoropyrimidin-4-yl)amino)butan-1-olwas prepared using a method similar to that described for thepreparation of Intermediate 473. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.82 (s,1H), 7.67 (s, 1H), 7.60 (d, J=8.9 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 5.35(s, 1H), 5.27 (m, 1H), 5.19 (m, 1H), 5.07 (m, 1H), 3.94 (m, 1H), 3.71(m, 2H), 1.57 (d, J=6.8 Hz, 3H), 1.21 (s, 9H), 1.14 (d, J=5.9 Hz, 3H).MS m/z 477.3 (M+H)⁺; Rt-0.96 min

Intermediate 475:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

Triphosgene (18 mg, 0.062 mmol, 0.5 equiv) was added to a solution of(2R,3R)-3-(tert-butoxy)-2-((6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)amino)butan-1-ol(57 mg, 0.12 mmol) in DCM (1.2 mL) at −78° C., followed by the dropwiseaddition of 2,6-lutidine (0.058 mL, 0.49 mmol, 4 equiv). The solutionwas allowed to warm to room temperature and was then heated at 35° C.for 30 min. The reaction was then cooled to room temperature and dilutedwith DCM (30 mL) and saturated aqueous sodium chloride (30 mL). Thelayers were separated and the organic layer was dried over Na₂SO₄,filtered and concentrated to give crude(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one,which was used without further purification. MS m/z 487.4 (M+H)⁺;Rt-1.12 min.

Intermediate 476:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-6-fluoropyrimidin-4-yl)oxazolidin-2-one

(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-6-fluoropyrimidin-4-yl)oxazolidin-2-onewas prepared using a method similar to that described for thepreparation of Intermediate 475. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.82 (s,1H), 7.66 (s, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H), 7.17(s, 1H), 5.31 (m, 1H), 4.70 (m, 1H), 4.62 (dd, J=9.2, 3.0 Hz, 1H), 4.33(m, 2H), 1.62 (d, J=6.8 Hz, 3H), 1.13 (br s, 9H), 1.02 (d, J=6.5 Hz,3H). MS m/z 503.3 (M+H)⁺; Rt-1.21 min.

Intermediate 477

To a microwave vial with a stir bar was added(R)-4-((R)-1-tert-butoxyethyl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one(43.6 mg, 0.145 mmol) and(S)-1-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)ethanamine (25.1 mg, 0.121mmol), followed by DMSO (605 uL) and DIEA (63.5 ul, 0.363 mmol). Thevial was capped and the reaction mixture heated in a preheated oil bathat 110° C. for 21 hr. The mixture was diluted with water and extractedwith EtOAc two times. The combined organic phases were washed withbrine, dried over sodium sulfate, filtered, concentrated and dried onhouse vacuum to afford crude(R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one,as a brown solid film, (yield assumed quantitative). LCMS m/z 471.4(M+H)⁺, Rt 0.85 min.

The compounds in Table 25 were prepared using methods similar to thosedescribed for the preparation of Intermediate 477.

TABLE 25 Intermediate: Name Structure LCMS 478:(R)-4-((R)-1-tert-butoxyethyl)-3-(2- ((S)-1-(3-isobutoxyphenyl)ethylamino)pyrimidin-4- yl)oxazolidin-2-one

MS m/z 457.4 (M + H)⁺, Rt 1.04 min. 479:(R)-4-((R)-1-tert-butoxyethyl)-3-(2- ((S)-1-(3-phenoxyphenyl)ethylamino)pyrimidin-4- yl)oxazolidin-2-one

MS m/z 477.3 (M + H)⁺, Rt 1.00 min. 480:(R)-4-((R)-1-tert-butoxyethyl)-3-(2- ((S)-1-(4-isopropoxyphenyl)ethylamino)pyrimidin- 4-yl)oxazolidin-2-one

MS m/z 443.4 (M + H)⁺, Rt 0.94 min. 481:(R)-4-((R)-1-tert-butoxyethyl)-3-(2- ((S)-1-(4-isobutoxy-3-methylphenyl)ethylamino)pyrimidin-4- yl)oxazolidin-2-one

MS m/z 471.4 (M + H)⁺, Rt 1.09 min. 482:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5- fluoro-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino) pyrimidin-4-yl)oxazolidin-2-one

MS m/z 487.3 (M + H)⁺, Rt 1.18 min. 483:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5- fluoro-2-(((S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)amino) pyrimidin-4-yl)oxazolidin-2-one

MS m/z 505.4 (M + H)⁺, Rt 1.16 min. 484:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4-(difluoromethoxy)phenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

MS m/z 469.3 (M + H)⁺, Rt 1.05 min. 485:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5- fluoro-2-(((S)-1-(3-fluoro-4-(trifluoromethoxy)phenyl)ethyl)amino) pyrimidin-4-yl)oxazolidin-2-one

MS m/z 505.4 (M + H)⁺, Rt 1.14 min. 486:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4-(difluoromethoxy)-3-fluorophenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)oxazolidin-2-one

MS m/z 487.3 (M + H)⁺, Rt 1.08 min. 487:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)oxazolidin-2-one

MS m/z 487.3 (M + H)⁺, Rt 1.04 min. 488:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(5- fluoro-2-(((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)amino) pyrimidin-4-yl)oxazolidin-2-one

MS m/z 487.3 (M + H)⁺, Rt 1.10 min. 489:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(3-(difluoromethoxy)phenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

MS m/z 469.3 (M + H)⁺, Rt 1.03 min.

Intermediate 490

To a microwave vial with a stir bar was added(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one(75.0 mg, 0.224 mmol) and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine(59.7 mg, 0.247 mmol), followed by DMSO (0.9 mL) and DIEA (118 ul, 0.673mmol). The vial was capped and the reaction mixture heated in apreheated oil bath at 85° C. for 2 hr. The mixture was diluted withbrine and extracted with EtOAc two times. The combined organic phaseswere dried over sodium sulfate, filtered, concentrated and dried onhouse vacuum to afford crude(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-oneas a brown solid film, (yield assumed quantitative). LCMS m/z 503.2(M+H)⁺, Rt 1.24 min.

The compounds in Table 26 were prepared using methods similar to thosedescribed for the preparation of Intermediate 490

TABLE 26 Intermediate: Name Structure LCMS 491:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6- chloro-2-(((S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)amino) pyrimidin-4-yl)oxazolidin-2-one

MS m/z 521.3 (M + H)⁺, Rt 1.33 min. 492:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6- chloro-2-(((S)-1-(4-(difluoromethoxy)phenyl)ethyl)amino) pyrimidin-4-yl)oxazolidin-2-one

MS m/z 485.2 (M + H)⁺, Rt 1.20 min. 493:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6- chloro-2-(((S)-1-(3-fluoro-4-(trifluoromethoxy)phenyl)ethyl)amino) pyrimidin-4-yl)oxazolidin-2-one

MS m/z 521.3 (M + H)⁺, Rt 1.31 min.

Intermediate 494

To a suspension of(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(30.0 mg, 0.106 mmol) and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine(38.4 mg, 0.159 mmol) in DMSO (0.53 mL), was added DIEA (64.7 ul, 0.371mmol) in a microwave vial. The vial was capped and the reaction mixtureheated in a preheated oil bath at 100° C. for 3 hr. The mixture wasdiluted with dilute brine and extracted with EtOAc two times. Thecombined organic phases were washed with brine, dried over magnesiumsulfate, filtered, concentrated and dried on house vacuum to affordcrude(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-oneas a clear colorless oil which was used without further purification(yield assumed quantitative). LCMS m/z 469.3 (M+H)⁺, Rt 0.98 min.

The compounds in Table 27 were prepared using methods similar to thosedescribed for the preparation of Intermediate 494.

TABLE 27 Intermediate: Name Structure LCMS 495:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(3-fluoro-4-(trifluoromethoxy)phenyl)ethyl)amino) pyrimidin-4-yl)oxazolidin-2-one

MS m/z 487.3 (M + H)⁺, Rt 0.99 min. 496:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)amino) pyrimidin-4-yl)oxazolidin-2-one

MS m/z 487.3 (M + H)⁺, Rt 1.00 min. 497:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4-(difluoromethoxy)-3-fluorophenyl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-one

MS m/z 469.4 (M + H)⁺, Rt 0.91 min. 498:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4-(cyclopropylmethoxy)phenyl)ethyl)amino) pyrimidin-4-yl)oxazolidin-2-one

MS m/z 455.3 (M + H)⁺, Rt 0.96 min. 499:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-one

MS m/z 475.3 (M + H)⁺, Rt 1.07 min. 500:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4-(difluoromethoxy)phenyl)ethyl)amino) pyrimidin-4-yl)oxazolidin-2-one

MS m/z 451.3 (M + H)⁺, Rt 0.90 min. 501:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(4-(difluoromethoxy)-2-fluorophenyl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-one

MS m/z 469.3 (M + H)⁺, Rt 0.90 min. 502:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)amino) pyrimidin-4-yl)oxazolidin-2-one

MS m/z 469.3 (M + H)⁺, Rt 0.94 min. 503:(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2- (((S)-1-(3-(difluoromethoxy)phenyl)ethyl)amino) pyrimidin-4-yl)oxazolidin-2-one

MS m/z 451.3 (M + H)⁺, Rt 0.87 min.

Intermediate 504(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

To a Parshaker flask were added benzyl4-((S)-1-((4-((R)-4-((S)-1-(tert-butoxy)ethyl)-2-oxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)piperidine-1-carboxylate(1 g, 1.90 mmole) and 20% Pd(OH)₂ in actived carbon (1 g, 1.42 mmole),then was added MeOH (100 mL) under nitrogen gas. The reaction mixturewas shaked under 50 spi hydrogen overnight. The reaction mixture wasfiltered through a celite. The celite cake was washed with MeOH and thefiltrate was concentrate in vacuo to afford the title product as a whitesolid (630 mg). ¹H NMR (400 MHz, CD₂Cl₂) δ 8.18-8.15 (m, 1H), 7.42-7.37(m, 1H), 4.99 (br, s, 1H), 4.77-4.70 (m, 1H), 4.64-4.57 (m, 1H),4.52-4.38 (m, 1H), 4.38-4.31 (m, 1H), 4.12-3.93 (m, 2H), 3.40-3.31 (m,1H), 3.12-3.29 (m, 2H), 2.81-2.70 (m, 1H), 2.02-1.29 (m, 5H), 1.25 (s,9H), 1.23-1.16 (m, 3H), 1.05-1.00 (m, 3H). HRMS(C) tR=2.65 min; MS m/z392.2655 (M+H)+

Intermediate 505(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

Intermediate 505 was prepared using a method similar to that describedfor the preparation of Intermediate 329. ¹H NMR (400 MHz, CD₂Cl₂) δ8.23-8.12 (m, 1H), 7.87 (d, J=7.45 Hz, 1H), 7.69 (d, J=6.22 Hz, 1H),6.81-6.74 (m, 2H), 4.67 (m, 1H), 4.61-4.55 (m, 1H), 4.37-4.29 (m, 1H),4.25-4.16 (m, 2H), 4.14-4.04 (m, 2H), 3.97-3.85 (m, 1H), 3.21-3.09 (m,2H), 2.11-1.87 (m, 3H), 1.61 (s, 6H), 1.39-1.23 (m, 1H), 1.21 (d, J=7.45Hz, 3H), 1.15-1.07 (m, 1H), 1.06 (s, 9H), 0.96 (d, J=6.62 Hz, 3H),HRMS(C) tR=4.80 min; MS m/z 579.3273 (M+H)+

Intermediate 506(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(4-chloro-3-(trifluoromethoxy)phenyl)piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

Intermediate 506 was prepared using a method similar to that describedfor the preparation of Intermediate 329. ¹H NMR (400 MHz, CD₂Cl₂) δ 8.17(br, s, 1H), 7.41 (d, J=6.14 Hz, 1H), 7.31 (d, J=7.98 Hz, 1H), 6.87-6.80(m, 2H), 4.77-4.71 (m, 1H), 4.64-4.58 (m, 1H), 4.49-4.40 (m, 1H),4.39-4.32 (m, 1H), 4.11-3.97 (m, 1H), 3.79-3.70 (m, 2H), 2.82-2.71 (m,2H), 2.04-1.91 (m, 1H), 1.90-1.80 (m, 1H), 1.66-1.35 (m, 3H), 1.34-1.15(m, 13H), 1.03 (d, J=7.36 Hz, 3H), HRMS(C) tR=5.68 min; MS m/z 586.2419(M+H)+

Intermediate 507 benzyl4-((S)-1-((4-((R)-4-((S)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)piperidine-1-carboxylate

Intermediate 507 was prepared using a method similar to that describedfor the preparation of Intermediate 342. ¹H NMR (400 MHz, CD₂Cl₂) δ 8.16(d, J=5.77 Hz, 1H), 7.41-7.31 (m, 6H), 5.15 (s, 2H), 4.76-4.71 (m, 1H),4.64-4.58 (m, 1H), 4.48-4.41 (m, 1H), 4.38-4.31 (m, 1H), 4.30-4.18 (m,2H), 4.09-3.96 (m, 1H), 2.77 (br s, 2H), 1.94-1.54 (m, 3H), 1.37-1.25(m, 3H), 1.23 (s, 9H), 1.20 (d, J=6.53 Hz, 3H), 1.03 (d, J=5.91 Hz, 3H).HRMS(C) tR=4.64 min; MS m/z 526.3012 (M+H)+

The intermediates in Table 27b were prepared using methods similar tothose described for the preparation of Intermediate 303.

TABLE 27b Intermediate: Name Structure LCMS 508:(S)-1-(1-(3,4-difluorophenyl)-1H- imidazol-4-yl)ethanamine

LCMS(B) m/z (M + H)⁺ 224.1, RT 0.39 min. 509:(S)-1-(1-(4-chloro-3-fluorophenyl)- 1H-imidazol-4-yl)ethanamine

LCMS(B) m/z (M + H)⁺ 240.0, RT 0.48 min. 510:(S)-1-(1-(3-chloro-4-fluorophenyl)- 1H-imidazol-4-yl)ethanamine

LCMS(B) m/z (M + H)⁺ 240.1, RT 0.46 min. 511:(S)-1-(1-(4-(difluoromethyl)phenyl)- 1H-imidazol-4-yl)ethanamine

LCMS(B) m/z (M + H)⁺ 238.1, RT 0.41 min. 512:(S)-1-(1-(4-(difluoromethyl)-3- fluorophenyl)-1H-imidazol-4-yl)ethanamine

LCMS(B) m/z (M + H)⁺ 256.0, RT 0.47 min. 513:(S)-1-(1-(3,5-difluoropehnyl)-1H- imidazol-4-yl)ethanamine

LCMS(B) m/z (M + H)⁺ 224.1, RT 0.41 min.

Intermediate 514(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(4-methoxybenzyl)oxazolidin-2-one

To a solution of benzyl((2R,3R)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (5.88 g, 19.9mmol) in 100 mL DMF was added NaH (60% in mineral oil, 1.62 g, 40.6mmol) at 0° C. The reaction mixture was stirred for 30 min at 0° C. Tothe reaction mixture were added 4-methoxybenzyl chloride (4.07 mL, 29.9mmol) and tetrabutylammonium iodide

(0.74 g, 1.99 mmol) and the resulting mixture was warmed to roomtemperature and stirred for 15.5 h. The reaction mixture was poured intoice water (200 mL) forming a white suspension. EtOAc (100 mL) was addedand the resulting mixture was stirred for 5 min to form a clear twolayer solution. After separation, the aqueous phase was extracted withEtOAc (100 mL×3). The combined organic solution was washed with brine(80 mL), dried over Na₂SO₄, filtered and concentrated. Flash columnchromatography (EtOAc/Heptane 0 to 70%) gave 5.90 g of the desiredproduct with minor impurities. Major product 1H NMR (400 MHz, MeOD) δ7.38-7.29 (m, 2H), 6.99-6.93 (m, 2H), 4.68-4.58 (m, 1H), 4.33 (dd,J=9.3, 4.5 Hz, 1H), 4.27-4.17 (m, 2H), 3.89 (dd, J=6.4, 4.8 Hz, 1H),3.81 (s, 3H), 3.65 (dd, J=9.0, 4.6 Hz, 1H), 1.26 (s, OH), 1.09 (s, 9H),1.02 (d, J=6.3 Hz, 3H). MS m/z 308.2 (M+H).

Intermediate 515(R)-4-((R)-1-hydroxyethyl)-3-(4-methoxybenzyl)oxazolidin-2-one

A solution of(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(4-methoxybenzyl)oxazolidin-2-one(5.90 g, 19.2 mmol) in CH₂Cl₂ (40 mL) was treated with TFA (40 mL) atroom temperature for 20 min. The reaction mixture was concentrated invacuo, then diluted with CH₂Cl₂ (˜50 mL), and again concentrated. Thisprocedure was repeated three times to remove TFA. Flash columnchromatography (EtOAc/Heptane 30˜100%) gave 3.81 g of the desiredproduct. 1H NMR (400 MHz, MeOD) δ 7.31-7.21 (m, 2H), 7.00-6.87 (m, 2H),4.67 (d, J=15.0 Hz, 1H), 4.34-4.18 (m, 3H), 3.95 (q, J=6.2 Hz, 1H), 3.80(s, 3H), 3.68 (dt, J=8.7, 5.5 Hz, 1H), 1.09 (d, J=6.4 Hz, 3H). MS m/z252.2 (M+H).

Intermediate 516(R)-4-((S)-1-fluoroethyl)-3-(4-methoxybenzyl)oxazolidin-2-one

To a cooled (0° C.) solution of(R)-4-((R)-1-hydroxyethyl)-3-(4-methoxybenzyl)oxazolidin-2-one (2.27 g,9.04 mmol) in 30 mL MeCN were added triethylamine (11.4 mL, 82 mmol)followed by perfluoro-1-butanesulfonyl fluoride (4.9 mL, 27.3 mmol) andNEt₃(HF)₃ (4.5 mL, 27.6 mmol) and the resulting mixture was stirred at0° C. for 70 min. The reaction mixture was diluted with water (60 mL)and extracted with EtOAc (3×60 mL). Combined organics were washed withwater (70 mL), brine (70 mL), dried over Na₂SO₄, filtered andconcentrated. Flash column chromatography (EtOAc/heptane 5 to 70%) gave2.19 g of the desired product. 1H NMR (400 MHz, CDCl3) δ 7.25-7.20 (m,2H), 6.92-6.83 (m, 2H), 4.87 (d, J=15.1 Hz, 1H), 4.75 (dqd, J=47.6, 6.6,2.1 Hz, 1H), 4.26 (td, J=9.2, 1.4 Hz, 1H), 4.17-4.05 (m, 2H), 3.81 (s,3H), 3.71 (dddd, J=19.8, 9.5, 5.8, 2.1 Hz, 1H), 1.29 (dd, J=23.1, 6.2Hz, 3H). MS m/z 254.5 (M+H).

Intermediate 517(R)-4-((S)-1-fluoroethyl)-3-(4-methoxybenzyl)oxazolidin-2-one

A solution of(R)-4-((S)-1-fluoroethyl)-3-(4-methoxybenzyl)oxazolidin-2-one (1.98 g7.8 mmol) in 40 mL TFA was heated at 65° C. for 16 h. The reactionmixture was concentrated to remove TFA. Flash column chromatography(EtOAc/CH₂Cl₂, 0 to 100%) gave 0.91 g pale brown solid. TLC (1:2heptane:EtOAc) Rf=0.25. 1H NMR (400 MHz, CDCl3) δ 5.60 (br s, 1H),4.72-4.54 (m, 1H), 4.51 (td, J=8.9, 0.9 Hz, 1H), 4.32 (dd, J=9.2, 4.8Hz, 1H), 4.02-3.88 (m, 1H), 1.38 (dd, J=24.0, 6.3 Hz, 3H).

Intermediate 518(R)-3-(2,5-difluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

Step 1: To a solution of(R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (6.35 g, 33.9 mmol) inDMF (170 mL) under a nitrogen atmosphere at 0° C. was added sodiumhydride (2.14 g, 50.9 mmol, 60%) portion wise over 3 minutes. Thereaction mixture was then stirred for 2 hr at 0° C. whereupon2,4,5-Trifluoropyrimidine (5 g, 37.3 mmol) was added and the reactionmixture allowed to stir 75 minutes at 0° C. then the mixture was allowedto warm to RT and stirred for 1 hr at RT. The reaction mixture wasquenched with the slow addition of saturated solution of NH₄Cl and theaqueous mixture extracted with EtOAc. Organic phases combined, washedwith water, brine, dried (Na₂SO₄), filtered and concentrated onto silicagel. Silica gel column chromatography (EtOAc/Heptane 0 to 50%) provideda colorless oil of(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one(6.97 g, 23.1 mmol, 68% yield) which crystallizes upon standing. ¹H NMR(400 MHz, CDCl₃)

1.10 (d, J=6.26 Hz, 3H) 1.18 (s, 9H) 4.25-4.35 (m, 1H) 4.49-4.62 (m, 2H)4.65-4.73 (m, 1H) 8.45 (d, J=1.57 Hz, 1H). LCMS m/z 246.1 (-t-butylfragment) (M+H)⁺, Rt 0.91 min.

Step 2: To a round bottom flask containing(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one(6.97 g, 23.1 mmol) was added DCM (23 mL) and TFA (23 mL). The resultingreaction mixture stirred for 1 hr at room temperature. The volatileswere then removed and the residue neutralized with a saturated solutionof NaHCO₃. The aqueous mixture was then extracted with EtOAc. Theorganic phases were combined, washed with water, brine, dried (Na₂SO₄),filtered and concentrated to a colorless residue of(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one(5.08 g, 20.7 mmol, 90% yield) which crystallizes upon standing. LCMSm/z 246.1 (M+H)⁺, Rt 0.34 min.

Step 3: To a round bottom flask containing a solution of(R)-3-(2,5-difluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one(4.64 g, 18.9 mmol) in Acetonitrile (63 mL) cooled to 0° C. was addedperfluorobutanesulfonyl fluoride (10.2 mL, 56.8 mmol) followed by theaddition of triethylamine trihydrofluoride (9.2 mL, 56.8 mmol) andtriethylamine (23.7 mL, 170 mmol). The resulting reaction mixtureallowed to stir at 0° C. for 4 hr. The reaction mixture was then dilutedwith water and the aqueous mixture was extracted with EtOAc. The organicphases combined, washed with water, brine, dried (Na₂SO₄), filtered andconcentrated onto silica gel. Silica gel column chromatography(EtOAc/Heptane 0 to 100%) provided a white crystalline of(R)-3-(2,5-difluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one(2.24 g, 8.97 mmol, 47% yield). ¹H NMR (400 MHz, CDCl₃)

8.50 (s, 1H), 5.00-5.25 (m, 1H), 4.75-4.92 (m, 1H), 4.54-4.68 (m, 2H),1.39 (dd, J=23.1, 7.0 Hz, 3H). LCMS m/z 248.0 (M+H)⁺, Rt 0.52 min.

The intermediates in Table 27c were prepared using a method similar tothat described for the preparation of Intermediate 247.

TABLE 27c

Intermediate 519

Intermediate 520

Intermediate 521

Intermediate 522

TABLE 27d Chemical name, NMR chemical shifts and LCMS signal for eachintermediate listed in Table 27c. Intermediate: Name ¹H NMR (400 MHz,CD₃OD) δ ppm LCMS 519: (S)-1-(1-(3,4- MS m/zdifluorophenyl)-1H-imidazol-4- 224.1 (M + H)⁺; yl)ethanaminehydrochloride Rt-0.40 min 520: (S)-1-(1-(3-chloro-4- MS m/zfluorophenyl)-1H-imidazol-4- 240.1 (M + H)⁺; yl)ethanamine hydrochlorideRt-0.46 min 521: (S)-1-(1-(4-chloro-3- MS m/zfluorophenyl)-1H-imidazol-4- 240.0 (M + H)⁺; yl)ethanamine hydrochlorideRt-0.48 min 522: (S)-1-(1-(4- MS m/z (difluoromethyl)-3-fluorophenyl)-256.0 (M − NH₂)⁺; 1H- imidazol-4-yl)ethanamine Rt-0.47 min hydrochloride

EXAMPLES Example 1(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

To a solution of 1-(3-(4-chlorophenyl)isoxazol-5-yl)ethanamine (610 mg,2.74 mmol) and(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(774 mg, 2.74 mmol) in DMSO (5 ml) was addedN-ethyl-N-isopropylpropan-2-amine (2 eq, 0.96 mL, 5.48 mmol) and heatedin a microwave at 120° C. for 2 hours. Dilute with EtOAc (50 ml), washwith water (50 ml), brine (50 ml), concentrate in vacuo. Flash columnchromatography (silica, 40 g) eluting w/ 0-25% EtOAc/DCM afforded 500 mgof white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=5.8, 1.6 Hz, 1H),7.80-7.65 (m, 2H), 7.58 (dd, J=5.8, 1.6 Hz, 1H), 7.49-7.37 (m, 2H),6.48-6.35 (m, 1H), 5.66-5.44 (m, 1H), 4.71 (dddd, J=9.8, 8.5, 4.6, 3.0Hz, 1H), 4.63 (ddd, J=9.4, 3.1, 2.1 Hz, 1H), 4.50-4.26 (m, 2H), 1.71 (s,1H), 1.25 (s, 5H), 1.15 (s, 5H), 1.03 (dd, J=22.4, 6.4 Hz, 3H),5.44-5.13 (m, 1H). HRMS(B) tR=3.36 min; m/z 485.1830

Example 2(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

To a solution of (S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethanamine 75 mg,0.337 mmol) and(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one(101 mg, 0.337 mmol) in DMSO (1 ml) was addedN-ethyl-N-isopropylpropan-2-amine (2 eq, 0.118 mL, 0.674 mmol) andheated in a microwave at 120° C. for 2 hours. Dilute with EtOAc (25 ml),wash with water (25 ml), brine (25 ml), concentrate in vacuo. Flashcolumn chromatography (silica, 40 g) eluting w/ 0-10% EtOAc/DCM afforded124 mg yellow foam: ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J=2.8 Hz, 1H),7.61-7.49 (m, 2H), 7.45-7.36 (m, 2H), 7.28 (d, J=6.2 Hz, 1H), 5.65 (d,J=8.9 Hz, 1H), 5.43-5.27 (m, 1H), 4.69 (qd, J=5.6, 2.9 Hz, 1H),4.62-4.35 (m, 2H), 4.23-4.01 (m, 1H), 1.68 (d, J=12.8 Hz, 2H), 1.26-1.16(m, 2H), 1.12 (s, 8H), 1.05 (d, J=6.4 Hz, 3H). HRMS(C) tR=1.55 min; m/z503.1736

Example 3

To a solution of(S)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethanamine(150 mg, 0.488 mmol) and(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(138 mg, 0.488 mmol) in DMSO (1 ml) was addedN-ethyl-N-isopropylpropan-2-amine (2 eq, 170 uL, 0.975 mmol) and heatedin a microwave at 115° C. for 2 hours. Dilute with EtOAc (25 ml), washwith water (25 ml), brine (25 ml), concentrate in vacuo. Flash columnchromatography (silica, 40 g) eluting w/ 0-5% EtOAc/DCM afforded 140 mg.¹H NMR (400 MHz, CDCl₃) δ 8.30-8.19 (m, 4H), 8.01 (dd, J=8.6, 2.1 Hz,2H), 7.54 (d, J=5.7 Hz, 2H), 7.45 (dq, J=8.4, 1.5 Hz, 2H), 4.53 (dd,J=9.3, 2.4 Hz, 2H), 4.05 (p, J=6.1 Hz, 1H), 3.51 (s, 5H), 1.80 (s, 1H),1.22 (t, J=6.5 Hz, 12H). Anal. RP-HPLC tR=2.73 min (Gradient: 2 to 98% Bin 4.4 min—flow 1 mL/min. Eluent A: Water+3.75 mM NH4Ac+0.001% formicacid. Eluent B: ACN. Column: Acquity CSH 1.7 μm 2.1×50 mm—50° C.) HRMSm/z 514.1039

The Following Examples were prepared using a method similar to thatdescribed for the preparation of Intermediate 342 or Example 3

Example 4:(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=5.6, 2.2 Hz, 3H), 7.96 (d, J=2.0Hz, 3H), 7.84 (dd, J=8.3, 2.1 Hz, 3H), 7.59 (dd, J=5.8, 3.0 Hz, 3H),7.46 (d, J=8.3 Hz, 3H), 5.71-5.42 (m, 3H), 5.32 (s, 1H), 4.75 (dtd,J=10.3, 5.2, 2.9 Hz, 3H), 1.67-1.60 (m, 3H), 4.64 (ddd, J=9.2, 6.2, 2.9Hz, 3H), 4.49-4.31 (m, 6H), 4.14 (q, J=7.1 Hz, 1H), 2.46 (s, 9H), 2.07(s, 1H), 1.77 (dd, J=6.8, 3.2 Hz, 9H), 1.27 (d, J=23.6 Hz, 29H), 1.05(dd, J=11.3, 6.5 Hz, 9H). HRMS(C) tR=2.00 min; MS m/z 500.98

Example 5(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-fluoro-3-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=5.8, 2.4 Hz, 3H), 8.02-7.83 (m,6H), 7.59 (dd, J=5.8, 2.9 Hz, 3H), 7.12 (t, J=8.9 Hz, 3H), 5.72-5.47 (m,5H), 5.32 (s, 1H), 4.75 (dtd, J=8.7, 4.8, 2.9 Hz, 3H), 4.64 (ddd, J=9.3,6.2, 2.9 Hz, 3H), 4.49-4.28 (m, 6H), 3.52 (s, 2H), 2.36 (d, J=2.0 Hz,9H), 1.78 (s, 2H), 1.65 (s, 3H), 1.30 (s, 22H), 1.24 (d, J=2.4 Hz, 6H),1.05 (dd, J=11.3, 6.4 Hz, 10H). HRMS(C) tR=1.95 min; m/z 484.2234

Example 6(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=5.8, 1.7 Hz, 3H), 7.74-7.57 (m,9H), 7.53-7.44 (m, 3H), 5.61 (qt, J=16.2, 9.7, 8.6 Hz, 7H), 5.32 (s,1H), 4.75 (ddd, J=8.6, 4.6, 2.9 Hz, 3H), 4.64 (ddd, J=8.8, 5.8, 2.9 Hz,3H), 4.50-4.30 (m, 6H), 4.14 (q, J=7.2 Hz, 2H), 4.01 (s, 9H), 2.07 (s,2H), 1.85-1.73 (m, 9H), 1.62 (s, 2H), 1.36-1.18 (m, 30H), 1.05 (dd,J=10.8, 6.5 Hz, 9H). HRMS(C) tR=1.61 min; m/z 516.1888

Example 7(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=5.8, 3.2 Hz, 1H), 8.11-7.93 (m,2H), 7.70-7.54 (m, 2H), 5.80-5.40 (m, 2H), 4.75 (dtd, J=8.6, 4.3, 2.2Hz, 1H), 1.67-1.60 (m, 1H), 4.64 (ddd, J=9.4, 4.2, 2.9 Hz, 1H),4.50-4.30 (m, 2H), 1.77 (dd, J=6.9, 3.4 Hz, 3H), 1.27 (d, J=21.9 Hz,9H), 1.06 (dd, J=9.8, 6.5 Hz, 3H). HRMS(C) tR=2.05 min; m/z 570.1605

Example 8(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J=5.7 Hz, 3H), 8.10 (d, J=1.3 Hz,3H), 7.84 (dd, J=8.3, 1.4 Hz, 3H), 7.71 (d, J=8.3 Hz, 3H), 7.64-7.55 (m,3H), 7.20 (d, J=3.1 Hz, 3H), 6.55 (dd, J=3.1, 0.8 Hz, 3H), 5.64 (p,J=7.2 Hz, 5H), 5.32 (s, 1H), 1.69-1.61 (m, 4H), 4.77 (ddd, J=8.7, 4.7,2.9 Hz, 3H), 4.65 (td, J=8.8, 8.4, 2.9 Hz, 3H), 4.52-4.27 (m, 6H), 3.90(s, 9H), 3.51 (s, 2H), 1.89-1.75 (m, 9H), 1.28 (d, J=23.5 Hz, 27H), 1.06(dd, J=10.9, 6.4 Hz, 10H). HRMS(C) tR=1.77 min; m/z 505.2437

Example 9(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 4.64 (ddd, J=9.9, 7.1, 2.9 Hz, 1H), 4.47-4.30(m, 2H), 1.06 (dd, J=9.3, 6.4 Hz, 3H), 1.85-1.72 (m, 3H), 1.63 (s, 1H),1.39 (s, 9H), 1.28 (d, J=21.1 Hz, 9H), 4.84-4.71 (m, 1H), 8.25 (d, J=5.7Hz, 1H), 8.11 (q, J=2.0 Hz, 1H), 7.89 (dt, J=7.7, 1.4 Hz, 1H), 7.66-7.52(m, 2H), 7.43 (t, J=7.8 Hz, 1H), 5.63 (p, J=7.3 Hz, 2H), 5.39-5.29 (m,OH). HRMS(C) tR=2.02 min; m/z 508.2798

Example 10(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=5.7, 2.9 Hz, 1H), 8.04 (dq, J=7.8,1.3 Hz, 1H), 7.95 (dt, J=2.5, 1.2 Hz, 1H), 7.67-7.49 (m, 2H), 7.39 (ddt,J=8.2, 2.5, 1.2 Hz, 1H), 5.62 (h, J=6.7, 6.1 Hz, 2H), 4.75 (dtd, J=9.1,4.7, 2.9 Hz, 1H), 4.64 (ddd, J=9.3, 4.9, 2.9 Hz, 1H), 4.49-4.26 (m, 2H),1.78 (dd, J=6.8, 3.6 Hz, 3H), 1.61 (s, 1H), 1.27 (d, J=23.8 Hz, 9H),1.06 (dd, J=10.0, 6.5 Hz, 3H). HRMS(C) tR=1.82 min; m/z 536.1995

Example 11(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-fluoro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=5.8, 3.3 Hz, 1H), 8.13-7.99 (m,2H), 7.60 (dd, J=5.8, 2.0 Hz, 1H), 5.72-5.56 (m, 1H), 5.48 (s, 1H),4.85-4.69 (m, 1H), 1.67-1.56 (m, 1H), 4.64 (ddd, J=9.5, 4.5, 2.9 Hz,1H), 4.53-4.28 (m, 2H), 1.77 (dd, J=7.0, 3.4 Hz, 3H), 1.27 (d, J=22.0Hz, 9H), 1.06 (dd, J=9.8, 6.4 Hz, 3H). HRMS(C) tR=1.87 min; m/z 554.1901

Example 12(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=5.9, 1.9 Hz, 1H), 8.09-7.92 (m,2H), 7.59 (dd, J=5.7, 3.1 Hz, 1H), 7.43-7.32 (m, 2H), 5.60 (dt, J=15.5,7.8 Hz, 2H), 4.75 (dtd, J=8.4, 5.0, 2.9 Hz, 1H), 4.64 (ddd, J=9.5, 7.1,2.9 Hz, 1H), 4.49-4.27 (m, 2H), 2.99 (hept, J=6.9 Hz, 1H), 1.76 (dd,J=7.0, 2.8 Hz, 3H), 1.60 (dd, J=6.9, 2.8 Hz, 1H), 1.40-1.19 (m, 15H),1.05 (dd, J=11.0, 6.5 Hz, 3H). HRMS(C) tR=2.23 min; m/z 494.2642

Example 13(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(1,2-dimethyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J=5.8 Hz, 1H), 7.91 (dd, J=7.5, 0.9Hz, 1H), 7.60 (d, J=5.8 Hz, 1H), 7.44 (dt, J=8.2, 1.1 Hz, 1H), 7.33-7.20(m, 1H), 6.99-6.89 (m, 1H), 5.66 (p, J=7.3 Hz, 1H), 4.77 (ddd, J=8.7,4.7, 3.0 Hz, 1H), 1.66-1.60 (m, 1H), 4.66 (dd, J=9.5, 3.0 Hz, 1H),4.53-4.44 (m, 1H), 4.38 (q, J=9.0, 8.3 Hz, 1H), 3.75 (s, 3H), 2.51 (d,J=0.9 Hz, 3H), 1.84-1.76 (m, 3H), 1.28 (d, J=26.5 Hz, 9H), 1.04 (d,J=6.5 Hz, 3H). HRMS(C) tR=1.65 min; MS m/z 519.60

Example 14(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

135 mg orangish-red resin (solidified upon standing). ¹H NMR (400 MHz,CDCl₃) δ 8.25 (d, J=5.7 Hz, 1H), 7.62-7.46 (m, 3H), 7.45-7.36 (m, 2H),4.85-4.69 (m, 1H), 4.64 (ddd, J=9.1, 5.6, 3.0 Hz, 1H), 4.44 (qd, J=6.4,4.6 Hz, 1H), 4.34 (dt, J=15.4, 9.0 Hz, 1H), 2.40 (d, J=1.3 Hz, 3H),1.79-1.60 (m, 3H), 1.34-1.18 (m, 11H), 1.04 (dd, J=14.8, 6.5 Hz, 3H).HRMS(C) tR=2.00 min; m/z 499.1986

Example 15(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=5.6, 2.2 Hz, 3H), 7.96 (d, J=2.0Hz, 3H), 7.84 (dd, J=8.3, 2.1 Hz, 3H), 7.59 (dd, J=5.8, 3.0 Hz, 3H),7.46 (d, J=8.3 Hz, 3H), 5.71-5.42 (m, 3H), 5.32 (s, 1H), 4.75 (dtd,J=10.3, 5.2, 2.9 Hz, 3H), 1.67-1.60 (m, 3H), 4.64 (ddd, J=9.2, 6.2, 2.9Hz, 3H), 4.49-4.31 (m, 6H), 4.14 (q, J=7.1 Hz, 1H), 2.46 (s, 9H), 2.07(s, 1H), 1.77 (dd, J=6.8, 3.2 Hz, 9H), 1.27 (d, J=23.6 Hz, 29H), 1.05(dd, J=11.3, 6.5 Hz, 9H). HRMS(C) tR=2.00 min; MS m/z 500.98

Example 16(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-fluoro-3-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=5.8, 2.4 Hz, 3H), 8.02-7.83 (m,6H), 7.59 (dd, J=5.8, 2.9 Hz, 3H), 7.12 (t, J=8.9 Hz, 3H), 5.72-5.47 (m,5H), 5.32 (s, 1H), 4.75 (dtd, J=8.7, 4.8, 2.9 Hz, 3H), 4.64 (ddd, J=9.3,6.2, 2.9 Hz, 3H), 4.49-4.28 (m, 6H), 3.52 (s, 2H), 2.36 (d, J=2.0 Hz,9H), 1.78 (s, 2H), 1.65 (s, 3H), 1.30 (s, 22H), 1.24 (d, J=2.4 Hz, 6H),1.05 (dd, J=11.3, 6.4 Hz, 10H). HRMS(C) tR=1.95 min; m/z 484.2234

Example 17(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=5.8, 1.7 Hz, 3H), 7.74-7.57 (m,9H), 7.53-7.44 (m, 3H), 5.61 (qt, J=16.2, 9.7, 8.6 Hz, 7H), 5.32 (s,1H), 4.75 (ddd, J=8.6, 4.6, 2.9 Hz, 3H), 4.64 (ddd, J=8.8, 5.8, 2.9 Hz,3H), 4.50-4.30 (m, 6H), 4.14 (q, J=7.2 Hz, 2H), 4.01 (s, 9H), 2.07 (s,2H), 1.85-1.73 (m, 9H), 1.62 (s, 2H), 1.36-1.18 (m, 30H), 1.05 (dd,J=10.8, 6.5 Hz, 9H). HRMS(C) tR=1.61 min; m/z 516.1888

Example 18(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chloro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=5.8, 3.2 Hz, 1H), 8.11-7.93 (m,2H), 7.70-7.54 (m, 2H), 5.80-5.40 (m, 2H), 4.75 (dtd, J=8.6, 4.3, 2.2Hz, 1H), 1.67-1.60 (m, 1H), 4.64 (ddd, J=9.4, 4.2, 2.9 Hz, 1H),4.50-4.30 (m, 2H), 1.77 (dd, J=6.9, 3.4 Hz, 3H), 1.27 (d, J=21.9 Hz,9H), 1.06 (dd, J=9.8, 6.5 Hz, 3H). HRMS(C) tR=2.05 min; m/z 570.1605

Example 19(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J=5.7 Hz, 3H), 8.10 (d, J=1.3 Hz,3H), 7.84 (dd, J=8.3, 1.4 Hz, 3H), 7.71 (d, J=8.3 Hz, 3H), 7.64-7.55 (m,3H), 7.20 (d, J=3.1 Hz, 3H), 6.55 (dd, J=3.1, 0.8 Hz, 3H), 5.64 (p,J=7.2 Hz, 5H), 5.32 (s, 1H), 1.69-1.61 (m, 4H), 4.77 (ddd, J=8.7, 4.7,2.9 Hz, 3H), 4.65 (td, J=8.8, 8.4, 2.9 Hz, 3H), 4.52-4.27 (m, 6H), 3.90(s, 9H), 3.51 (s, 2H), 1.89-1.75 (m, 9H), 1.28 (d, J=23.5 Hz, 27H), 1.06(dd, J=10.9, 6.4 Hz, 10H). HRMS(C) tR=1.77 min; m/z 505.2437

Example 20(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 4.64 (ddd, J=9.9, 7.1, 2.9 Hz, 1H), 4.47-4.30(m, 2H), 1.06 (dd, J=9.3, 6.4 Hz, 3H), 1.85-1.72 (m, 3H), 1.63 (s, 1H),1.39 (s, 9H), 1.28 (d, J=21.1 Hz, 9H), 4.84-4.71 (m, 1H), 8.25 (d, J=5.7Hz, 1H), 8.11 (q, J=2.0 Hz, 1H), 7.89 (dt, J=7.7, 1.4 Hz, 1H), 7.66-7.52(m, 2H), 7.43 (t, J=7.8 Hz, 1H), 5.63 (p, J=7.3 Hz, 2H), 5.39-5.29 (m,OH). HRMS(C) tR=2.02 min; m/z 508.2798

Example 21(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=5.7, 2.9 Hz, 1H), 8.04 (dq, J=7.8,1.3 Hz, 1H), 7.95 (dt, J=2.5, 1.2 Hz, 1H), 7.67-7.49 (m, 2H), 7.39 (ddt,J=8.2, 2.5, 1.2 Hz, 1H), 5.62 (h, J=6.7, 6.1 Hz, 2H), 4.75 (dtd, J=9.1,4.7, 2.9 Hz, 1H), 4.64 (ddd, J=9.3, 4.9, 2.9 Hz, 1H), 4.49-4.26 (m, 2H),1.78 (dd, J=6.8, 3.6 Hz, 3H), 1.61 (s, 1H), 1.27 (d, J=23.8 Hz, 9H),1.06 (dd, J=10.0, 6.5 Hz, 3H). HRMS(C) tR=1.82 min; m/z 536.1995

Example 22(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-fluoro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=5.8, 3.3 Hz, 1H), 8.13-7.99 (m,2H), 7.60 (dd, J=5.8, 2.0 Hz, 1H), 5.72-5.56 (m, 1H), 5.48 (s, 1H),4.85-4.69 (m, 1H), 1.67-1.56 (m, 1H), 4.64 (ddd, J=9.5, 4.5, 2.9 Hz,1H), 4.53-4.28 (m, 2H), 1.77 (dd, J=7.0, 3.4 Hz, 3H), 1.27 (d, J=22.0Hz, 9H), 1.06 (dd, J=9.8, 6.4 Hz, 3H). HRMS(C) tR=1.87 min; m/z 554.1901

Example 23(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=5.9, 1.9 Hz, 1H), 8.09-7.92 (m,2H), 7.59 (dd, J=5.7, 3.1 Hz, 1H), 7.43-7.32 (m, 2H), 5.60 (dt, J=15.5,7.8 Hz, 2H), 4.75 (dtd, J=8.4, 5.0, 2.9 Hz, 1H), 4.64 (ddd, J=9.5, 7.1,2.9 Hz, 1H), 4.49-4.27 (m, 2H), 2.99 (hept, J=6.9 Hz, 1H), 1.76 (dd,J=7.0, 2.8 Hz, 3H), 1.60 (dd, J=6.9, 2.8 Hz, 1H), 1.40-1.19 (m, 15H),1.05 (dd, J=11.0, 6.5 Hz, 3H). HRMS(C) tR=2.23 min; m/z 494.2642

Example 24(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(1,2-dimethyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J=5.8 Hz, 1H), 7.91 (dd, J=7.5, 0.9Hz, 1H), 7.60 (d, J=5.8 Hz, 1H), 7.44 (dt, J=8.2, 1.1 Hz, 1H), 7.33-7.20(m, 1H), 6.99-6.89 (m, 1H), 5.66 (p, J=7.3 Hz, 1H), 4.77 (ddd, J=8.7,4.7, 3.0 Hz, 1H), 1.66-1.60 (m, 1H), 4.66 (dd, J=9.5, 3.0 Hz, 1H),4.53-4.44 (m, 1H), 4.38 (q, J=9.0, 8.3 Hz, 1H), 3.75 (s, 3H), 2.51 (d,J=0.9 Hz, 3H), 1.84-1.76 (m, 3H), 1.28 (d, J=26.5 Hz, 9H), 1.04 (d,J=6.5 Hz, 3H). HRMS(C) tR=1.65 min; MS m/z 519.60

Example 25(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

135 mg orange-red resin (solidified upon standing). ¹H NMR (400 MHz,CDCl₃) δ 8.25 (d, J=5.7 Hz, 1H), 7.62-7.46 (m, 3H), 7.45-7.36 (m, 2H),4.85-4.69 (m, 1H), 4.64 (ddd, J=9.1, 5.6, 3.0 Hz, 1H), 4.44 (qd, J=6.4,4.6 Hz, 1H), 4.34 (dt, J=15.4, 9.0 Hz, 1H), 2.40 (d, J=1.3 Hz, 3H),1.79-1.60 (m, 3H), 1.34-1.18 (m, 11H), 1.04 (dd, J=14.8, 6.5 Hz, 3H).HRMS(C) tR=2.00 min; m/z 499.1986

Example 26(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(4-(4-chlorophenyl)-5-methylthiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one

200 mg (white solid). ¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=2.9, 1.0 Hz,1H), 7.68-7.52 (m, 2H), 7.47-7.35 (m, 2H), 5.99-5.65 (m, 1H), 5.49-5.20(m, 1H), 4.67 (ddt, J=21.5, 8.9, 5.4 Hz, 1H), 4.58-4.40 (m, 2H),4.22-4.05 (m, 1H), 2.53 (d, J=6.0 Hz, 3H), 1.74 (s, 1H), 1.16 (s, 5H),1.13-1.05 (m, 6H), 1.01 (d, J=6.4 Hz, 3H). HRMS(B) tR=5.16 min; m/z534.1744

Example 27(4R)-3-(2-((1-(4-(4-bromophenyl)thiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one

210 mg (white solid). ¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=2.9, 1.9 Hz,1H), 7.87-7.71 (m, 2H), 7.62-7.50 (m, 2H), 7.40 (d, J=8.7 Hz, 1H), 5.85(d, J=15.8 Hz, 1H), 5.58-5.36 (m, 1H), 4.81-4.57 (m, 1H), 4.57-4.39 (m,2H), 4.23-4.00 (m, 1H), 2.07 (s, 2H), 1.77 (s, 1H), 1.16 (s, 5H), 1.11(d, J=6.4 Hz, 2H), 1.06 (s, 5H), 0.98 (d, J=6.4 Hz, 2H). HRMS(B) tR=5.15min; m/z 566.1079 (M+H).

Example 28(R)-3-(2-(((S)-1-(1-(4-chloro-3-(trifluoromethoxy)phenyl)piperidin-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one

(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(4-chloro-3-(trifluoromethoxy)phenyl)piperidin-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one(34 mg, 0.058 mmole) was dissolved in DCM (1 mL), TFA (1 mL) was added.The reaction solution was stirred for 2 hour at room temperature and wasconcentrated by rotary evaporation. The resulting residue was dissolvedin DCM (2 mL) and water 2 mL) and the pH was adjusted to ˜9 with NH4OH.The DCM layer was separated and concentrated by rotary evaporation toafford 28 mg of the title product as a yellow oil (ratio of two peakswith same MS: 96/4% by LC-MS). (400 MHz, CD₂Cl₂) δ 8.22 (d, J=2.27 Hz,1H), 7.31 (d, J=8.85 Hz, 1H), 6.88-6.79 (m, 2H), 5.12 (br s, 1H),4.61-4.50 (m, 2H), 4.46-4.37 (m, 1H), 4.26-4.15 (m, 1H), 3.93 (br s,1H), 3.77-3.68 (m, 2H), 3.20 (br s, 1H), 2.79-2.67 (m, 2H), 1.96-1.78(m, 2H), 1.70-1.58 (m, 1H), 1.55-1.28 (m, 2H), 1.23 (d, J=6.63 Hz, 3H),1.19 (d, J=7.19 Hz, 3H), HRMS(C) tR=4.47 min; MS m/z 548.1689 (M+H)+

Example 29(R)-3-(5-fluoro-2-(((S)-1-(1-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one

A cloudy solution of(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-(((S)-1-(piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (21 mg, 0.051 mmol),4-bromo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine (14 mg, 0.051mmol), Pd(OAc)₂ (1 mg, 5 umol), BINAP (3 mg, 5 umol), and Cs₂CO₃ (25 mg,0.077 mmol) in 6 mL toluene was heated at 90° C. overnight. The mixturewas cooled to room temperature, and filtered through Celite. The celitecake was rinsed with 5 mL EtOAc. The filtrate was poured into 5 mLwater. Organic layer was separated, and the aqueous was furtherextracted with EtOAc (5 mL). The organic extracts were combined andconcentrated by rotary evaporation. The resulting crude was dissolved inDCM (1 mL), TFA (1 mL) was added. The reaction solution was stirred for2 hour at room temperature and was concentrated by rotary evaporation.The resulting residue was dissolved in DCM (2 mL) and water (2 mL) andthe pH was adjusted to ˜9 with NH4OH. The DCM layer was separated andconcentrated by rotary evaporation. The crude was dissolved in a mixtureof MeOH (1 mL) and DMSO (1 mL) and purified by reverse phase HPLC.Selected fractions were collected and concentrated by rotary evaporationto afford the title product as a colorless oil (5 mg) (ratio of twopeaks with same MS: 93/7% by LC-MS). (400 MHz, CD₂Cl₂) δ 8.16-8.08 (m,2H), 6.79-6.75 (m, 1H), 6.57-6.52 (m, 1H), 4.97-4.86 (m, 1H), 4.47-4.39(m, 2H), 4.33-4.25 (m, 1H), 4.11-4.02 (m, 1H), 3.89-3.75 (m, 3H), 2.97(br s, 1H), 2.80-2.67 (m, 2H), 1.84-1.67 (m, 2H), 1.67-1.55 (m, 1H),1.48 (s, 6H), 1.38-1.15 (m, 2H), 1.11 (d, J=5.91 Hz, 3H), 1.07 (d,J=5.91 Hz, 3H), HRMS(C) tR=3.59 min; MS m/z 541.2557 (M+H)+

Examples 30, 31, 32, and 333-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one

To a solution of (S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethanamine 72 mg,0.322 mmol) and3-(2-fluoropyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one(90 mg, 0.322 mmol) in DMSO (1 ml) was addedN-ethyl-N-isopropylpropan-2-amine (2 eq, 0.113 mL, 0.645 mmol) andheated in a microwave at 120° C. for 2 hours. Dilute with EtOAc (25 ml),wash with water (25 ml), brine (25 ml), concentrate in vacuo. Flashcolumn (silica, 40 g, 50μ) eluting w/ 0-5% EtOAc/DCM followed by Flashcolumn (silica, 80 g, 15μ) eluting w/ 0-5% EtOAc/heptane separated 2major peaks which were further separated via chiral SFC chromatographyon an ID column (75 g/min, 120 bar, 21×250 mm) eluting 35% IPA/CO₂ (v/v)to give:

Example 30, Peak 1: 10 mg (white foam): ¹H NMR (400 MHz, CDCl₃) δ 8.27(d, J=5.8 Hz, 1H), 8.09-7.95 (m, 2H), 7.58 (d, J=5.7 Hz, 1H), 7.54-7.41(m, 2H), 5.83 (s, 1H), 5.28 (s, 1H), 4.72 (s, 1H), 4.54 (dd, J=9.6, 2.5Hz, 1H), 4.37 (d, J=9.5 Hz, 1H), 3.44-3.15 (m, 1H), 1.78 (d, J=7.0 Hz,3H), 1.63 (s, 1H), 1.32 (d, J=7.3 Hz, 3H), 1.23 (d, J=6.1 Hz, 3H). HRMSm/z 482.1081, RT=2.90 min. Chiral RT=2.15 min

Example 31, Peak 2: 38 mg (white foam): ¹H NMR (400 MHz, CDCl₃) δ 8.27(d, J=5.7 Hz, 1H), 8.09-7.93 (m, 2H), 7.58 (d, J=5.7 Hz, 1H), 7.53-7.41(m, 2H), 5.84 (s, 1H), 5.33 (s, 1H), 4.72 (s, 1H), 4.55 (dd, J=9.6, 2.4Hz, 1H), 4.35 (t, J=8.8 Hz, 1H), 3.39-3.17 (m, 1H), 1.78 (d, J=7.0 Hz,3H), 1.62 (d, J=6.9 Hz, 1H), 1.32 (d, J=7.3 Hz, 3H), 1.23 (d, J=6.2 Hz,1H). HRMS m/z 482.1081, RT=2.89 min. Chiral RT=2.43 min

Example 32, Peak 3: 45 mg (white foam)¹H NMR (400 MHz, CDCl₃) δ 8.27 (d,J=5.8 Hz, 1H), 8.09-7.91 (m, 2H), 7.59 (d, J=5.7 Hz, 1H), 7.52-7.38 (m,2H), 6.22 (s, 1H), 5.38 (d, J=48.6 Hz, 1H), 4.86 (dd, J=8.2, 4.2 Hz,1H), 1.83-1.75 (m, 3H), 4.56 (dd, J=9.3, 2.5 Hz, 1H), 4.43 (t, J=9.2 Hz,1H), 3.50 (s, 1H), 2.97 (d, J=46.0 Hz, 1H), 1.23 (d, J=6.2 Hz, 1H), 1.12(d, J=7.6 Hz, 3H). HRMS m/z 482.1081, RT=2.86 min. Chiral RT=2.55 min

Example 33, Peak 4: 12 mg (white foam)¹H NMR (400 MHz, CDCl₃) δ 8.28 (d,J=5.8 Hz, 1H), 8.11-7.92 (m, 2H), 7.60 (d, J=5.6 Hz, 1H), 7.53-7.40 (m,2H), 5.77 (s, 1H), 5.45 (s, 1H), 4.96-4.77 (m, 1H), 4.57 (dd, J=9.5, 2.4Hz, 1H), 4.44 (t, J=9.1 Hz, 1H), 2.94 (s, 1H), 1.79 (d, J=7.1 Hz, 3H),1.63 (d, J=7.1 Hz, 1H), 1.23 (d, J=6.1 Hz, 2H), 1.20-1.08 (m, 3H). HRMSm/z 482.1081, RT=2.86 min. Chiral RT=2.66 min

Example 343-(5-fluoro-2-(((S)-1-(3-fluoro-4-(hydroxymethyl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one

To a solution of (S)-(4-(1-aminoethyl)-2-fluorophenyl)methanol (62.6 mg,0.37 mmol) and3-(2-fluoropyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one(110 mg, 0.37 mmol) in DMSO (1 ml) was addedN-ethyl-N-isopropylpropan-2-amine (2 eq, 0.129 mL, 0.74 mmol) and heatedin a microwave at 120° C. for 2 hours. Dilute with EtOAc (25 ml), washwith water (25 ml), brine (25 ml), concentrate in vacuo. Flash column(silica, 40 g, 50μ) eluting w/ 5-50% EtOAc/DCM afforded 155 mg (whitefoam): ¹H NMR (400 MHz, CDCl₃) δ 8.22 (dd, J=6.6, 2.6 Hz, 1H), 7.40 (td,J=7.8, 5.2 Hz, 1H), 7.12 (ddd, J=7.8, 4.6, 1.6 Hz, 1H), 7.03 (ddd,J=10.9, 6.3, 1.7 Hz, 1H), 5.52 (d, J=22.7 Hz, 1H), 4.90 (p, J=7.0 Hz,1H), 4.75 (d, J=9.6 Hz, 3H), 4.59 (dt, J=15.7, 9.1 Hz, 1H), 4.41 (ddd,J=12.4, 9.1, 6.2 Hz, 1H), 1.89 (d, J=18.6 Hz, 1H), 1.16 (d, J=7.2 Hz,1H), 1.04-0.74 (m, 2H). HRMS m/z 446.1377, RT=2.03 min.

Example 35

A solution of(R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one(18.6 mg, 0.082 mmol) and1-(5-(2,3-dichlorophenyl)pyrimidin-2-yl)ethanamine (22 mg, 0.082 mmol)in DMSO (2 mL) was heated at 100° C. for 2 h. The reaction mixture waspoured into water (20 mL), and extracted with EtOAc (2×20 mL). Combinedorganics were dried over Na₂SO₄, filtered and concentrated. Silica gelcolumn chromatography ((25% MeOH in EtOAc)/Heptane 10 to 100%) provided(4R)-3-(2-(1-(5-(2,3-dichlorophenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one(12 mg, approx 1:1 mixture of diastereomers) as a white solid. ¹H NMR(400 MHz, CDCl₃) δ 8.72 (s, 4H), 8.15 (d, J=5.7 Hz, 2H), 7.51 (ddd,J=8.1, 2.8, 1.6 Hz, 2H), 7.40-7.11 (m, 6H), 6.07-5.96 (m, 2H), 5.32 (t,J=7.4 Hz, 1H), 5.09 (s, 1H), 4.81 (s, 1H), 4.68 (s, 1H), 4.43 (dd,J=7.3, 4.8 Hz, 2H), 4.33 (dd, J=9.4, 8.3 Hz, 1H), 4.18 (d, J=9.0 Hz,2H), 3.62 (s, 1H), 3.23 (s, 1H), 1.62-1.58 (m, 6H), 1.07-0.97 (m, 3H),0.87-0.77 (m, 3H). HRMS m/z 475.1039 and 475.1042 (M+H)⁺.

Example 36(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

A solution of(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one(68 mg, 0.18 mmol) in 3 ml of DCM was cooled to 0° C., treated with 1 mlof TFA, it was stirred at same temperature for 4 hours, the solvent wasremoved to yield the product as a TFA salt form, it was dissolved in 2ml of MeOH, the TFA was removed by using a PL-HCO3 MP SPE (0.9 mmol)cartridge, the solvent was removed to yield the pure product(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-oneas a white solid (52 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, J=5.8 Hz,1H), 7.43 (d, J=5.8 Hz, 1H), 7.40-7.31 (m, 4H), 7.31-7.24 (m, 1H), 5.84(s, 1H), 4.94 (s, 1H), 4.58 (q, J=4.9, 3.2 Hz, 1H), 4.40 (dd, J=9.3, 2.8Hz, 1H), 4.31 (t, J=8.9 Hz, 1H), 1.56 (d, J=7.0 Hz, 3H), 0.98-0.74 (m,3H). HRMS m/z 329.1619 (M+H)⁺, RT=2.23 min.

Example 37 and 38

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one(97 mg, 0.17 mmol) was treated with 90% TFA/water for 2 hours.Concentrate in vacuo and neutralized by passing through a column ofMP-carbonate resin (2.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOHafforded 58 mg of(R)-3-(2-(((R)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-(1-hydroxyethyl)oxazolidin-2-oneas a waxy off-white foam. Separated the diastereomers via chiral SFCchromatography on an AD-H column (75 g/min, 120 bar, 21×250 mm) eluting25% IPA/CO₂ (v/v) to give(R)-3-(2-(((R)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-oneand(R)-3-(2-(((S)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

Example 37 Peak 1: 23 mg (off-white foam). ¹H NMR (400 MHz, CDCl₃) δ8.32-8.17 (m, 4H), 8.01 (dd, J=8.6, 2.1 Hz, 2H), 7.54 (d, J=5.7 Hz, 2H),7.45 (dq, J=8.4, 1.5 Hz, 2H), 6.16 (s, 2H), 5.32 (s, 3H), 4.82-4.60 (m,2H), 4.53 (dd, J=9.3, 2.4 Hz, 2H), 4.43 (s, 2H), 4.29 (q, J=8.9 Hz, 2H),4.05 (p, J=6.1 Hz, 1H), 3.51 (s, 5H), 1.80 (s, 1H), 1.22 (t, J=6.5 Hz,12H). HRMS(B) tR=2.75 min. MS m/z 514.0979 Chiral RT=2.10 min

Example 38 Peak 2: 58 mg (off-white foam). ¹H NMR (400 MHz, CDCl₃) δ8.23 (dd, J=12.4, 3.9 Hz, 8H), 8.01 (dd, J=8.5, 2.1 Hz, 4H), 7.71-7.36(m, 8H), 6.29 (s, 4H), 5.37 (d, J=37.2 Hz, 5H), 4.86 (ddd, J=7.7, 4.9,2.4 Hz, 4H), 4.55 (dd, J=9.5, 2.6 Hz, 4H), 4.41 (t, J=8.9 Hz, 4H),4.19-3.77 (m, 5H), 3.51 (s, 3H), 1.83 (s, 1H), 1.23 (d, J=6.1 Hz, 4H),1.12-0.95 (m, 12H). HRMS(B) tR=2.73 min. MS m/z 514.0979 Chiral RT=3.70min

The compounds in Table 28a were prepared using methods similar to thosedescribed for the preparation of Examples 35, 36, or 37/38.

TABLE 28a

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

TABLE 28b Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 28a. Example: Name ¹H NMR (400 MHz) δ ppm LCMS39: (4R)-3-(2-(1-(5-(5-fluoro-2- (CDCl₃) δ 8.71 (d, J = 1.8 Hz, 4H),HRMS (B) methylphenyl)pyrimidin-2- 8.23 (dd, J = 5.8, 1.0 Hz, 2H), 7.44m/z yl)ethylamino)pyrimidin-4-yl)-4-((R)-1- (dd, J = 12.1, 5.7 Hz, 2H),7.35-7.26 439.1865 hydroxyethyl)oxazolidin-2-one (m, 3H), 7.08 (tt, J =8.4, 2.8 Hz, 2H), and 6.95 (dt, J = 9.0, 2.7 Hz, 2H), 6.16 (t, 439.1865J = 8.5 Hz, 2H), 5.41 (p, J = 7.0 Hz, (M + H)⁺ 1H), 5.20 (s, 1H), 4.91(s, 1H), 4.78 (s, 1H), 4.58-4.49 (m, 2H), 4.42 (dd, J = 9.4, 8.3 Hz,2H), 4.29 (s, 2H), 3.84 (s, 1H), 3.48 (br s, 1H), 2.27 (s, 6H), 1.95 (brs, 2H), 1.71-1.67 (m, 3H), 1.38-1.18 (m, 6H), 1.12 (br s, 3H) (approx1:1 mixture of diastereomers) 40: (4R)-4-((R)-1-hydroxyethyl)-3-(2-(CDCl₃) δ 8.95 (s, 4H), 8.41 (d, J = HRMS (B) ((1-(5-(4- 5.8, 1H), 8.21(d, J = 5.8 Hz, 1H), 7.92- m/z (trifluoromethyl)phenyl)pyrimidin-2- 7.66(m, 7H), 7.48-7.44 (m, 3H), 475.1684 yl)ethyl)amino)pyrimidin-4-6.45-6.35 (m, 2H), 5.41 (p, J = 6.9 (M + H)⁺ yl)oxazolidin-2-one Hz,1H), 5.22 (br s, 1H), 4.94-4.90 (m, 2H), 4.78 (br s, 1H), 4.65-4.35 (m,4H), 4.30 (br s, 1H), 3.49 (br s, 1H), 2.77 (br s, 1H), 1.70-1.66 (m,6H), 1.25-1.21 (m, 3H), 1.09 (br s, 3H) (approx 1:1 mixture ofdiastereomers) 41: (4R)-3-(2-(1-(5-(4-fluoro-3- (CDCl₃) δ 8.85-8.75 (m,4H), 8.16- HRMS (B) methylphenyl)pyrimidin-2- 8.08 (m, 2H), 7.38-7.20(m, 6H), m/z yl)ethylamino)pyrimidin-4-yl)-4-((R)-1- 7.09-7.05 (m, 2H),6.08-6.04 (m, 439.1875 hydroxyethyl)oxazolidin-2-one 2H), 5.34-5.25 (m,1H), 5.14-5.10 (M + H)⁺. (m, 1H), 4.86-4.78 (m, 1H), 4.57 (dd, J = 9.5,2.8 Hz, 1H), 4.49-4.28 (m, 3H), 3.54 (br s, 1H), 2.29 (br s, 6H),1.58-1.53 (m, 6H), 1.19-1.12 (m, 3H), 1.00 (br s, 3H) (approx 1:1mixture of diastereomers) 42: (4R)-3-(2-((1-(5-(tert- (CDCl₃) δ8.74-8.72 (m, 4H), 8.20 (d, HRMS (B) butyl)pyrimidin-2- J = 5.8 Hz, 2H),7.46-7.40 (m, 2H), m/z yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-6.19-6.15 (m, 2H), 5.37-5.29 (m, 387.2135 hydroxyethyl)oxazolidin-2-one1H), 5.30 (s, 1H), 4.98-4.86 (m, 1H), (M + H)⁺ 4.82 (s, 1H), 4.61-4.50(m, 3H), 4.47- 4.37 (m, 2H), 4.32-4.21 (m, 2H), 3.84 (s, 1H), 1.63-1.58(m, 6H), 1.39- 1.37 (m, 18H), 1.24-1.20 (m, 3H), 1.14-1.00 (m, 3H)(approx 1:1 mixture of diastereomers) 43:(4R)-4-((R)-1-hydroxyethyl)-3-(2- (CDCl₃) δ 8.94 (d, J = 4.4 Hz, 4H),HRMS (B) (1-(5-(3- 8.23 (dd, J = 5.8, 2.2 Hz, 2H), 7.86- m/z(trifluoromethyl)phenyl)pyrimidin-2- 7.63 (m, 8H), 7.44 (dd, J = 13.5,5.7 475.1682 yl)ethylamino)pyrimidin-4- Hz, 2H), 6.12 (dd, J = 15.1, 7.4Hz, and yl)oxazolidin-2-one 2H), 5.41 (t, J = 7.4 Hz, 1H), 5.20 (br475.1689 s, 1H), 4.89 (d, J = 6.7 Hz, 1H), 4.80 (M + H)⁺. (s, 1H),4.58-4.48 (m, 2H), 4.43 (dd, J = 9.3, 8.2 Hz, 2H), 4.30 (br s, 1H), 3.77(br s, 1H), 3.36 (br s, 1H), 1.90 (br s, 3H), 1.69 (d, J = 2.2 Hz, 3H),1.37-1.17 (m, 3H), 1.12 (br s, 3H) (approx 1:1 mixture of diastereomers)44: (R)-4-((R)-1-hydroxyethyl)-3-(2- (CDCl₃) δ 8.21 (d, J = 5.9 Hz, 1H),HRMS (B) (((S)-1-(4-phenoxyphenyl)ethyl)amino) 7.45 (d, J = 5.7 Hz, 1H),7.42-7.26 m/z pyrimidin-4-yl)oxazolidin-2-one (m, 4H), 7.13 (dd, J =8.1, 6.7 Hz, 421.1875, 1H), 7.07-6.88 (m, 4H), 5.66 (b, 1H), (M + H)⁺,4.97 (s, 1H), 4.67 (ddd, J = 8.2, 5.1, RT = 2.56 2.5 Hz, 1H), 4.51-4.25(m, 2H), 3.61 min. (b, 1H), 1.56 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 22.9Hz, 3H). 45: (4R)-3-(2-((1-(5-(4- HRMS (B) fluorophenoxy)pyrimidin-2-m/z yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 441.1676,hydroxyethyl)oxazolidin-2-one (M + H)⁺, RT = 2.13 min. 46:(4R)-3-(2-((1-(3-(4-chlorophenyl)- HRMS (B) 1,2,4-oxadiazol-5- m/zyl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- 431.1219,hydroxyethyl)oxazolidin-2-one. (M + H)⁺, RT = 2.16 min. 47:(R)-4-((R)-1-hydroxyethyl)-3-(2- ¹H NMR (400 MHz, MeOD) δ 9.13 (d, HRMSm/z (((S)-1-(5-(3- J = 1.5 Hz, 1H), 8.73 (d, J = 1.4 Hz, 475.1686(trifluoromethyl)phenyl)pyrazin-2- 1H), 8.39 (s, 1H), 8.32 (d, J = 7.9Hz, (M + H)⁺. yl)ethyl)amino)pyrimidin-4- 1H), 8.16 (d, J = 5.9 Hz, 1H),7.78 (d, yl)oxazolidin-2-one J = 7.8 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H),7.39 (d, J = 5.8 Hz, 1H), 5.28 (q, J = 7.0 Hz, 1H), 4.51 (dd, J = 9.2,2.8 Hz, 1H), 4.39 (t, J = 8.9 Hz, 1H), 3.81 (br s, 0H), 1.65 (d, J = 7.1Hz, 3H), 0.80 (br s, 3H); 48: (R)-3-(2-((S)-1-(3-fluoro-4-((3,3,4- ¹HNMR (400 MHz, MeOD) δ 8.11 (d, HRMS m/z trimethylpiperazin-1- J = 5.8Hz, 1H), 7.40-7.30 (m, 2H), 487.2808yl)methyl)phenyl)ethylamino)pyrimidin- 7.16 (dd, J = 8.0, 1.7 Hz, 1H),7.07 (M + H)⁺. 4-yl)-4-((S)-1-hydroxyethyl)oxazolidin- (dd, J = 11.2,1.7 Hz, 1H), 5.08 (q, J = 2-one 7.0 Hz, 1H), 4.80 (br s, 1H), 4.52 (dd,J = 9.2, 2.8 Hz, 1H), 4.38 (t, J = 8.9 Hz, 1H), 3.99 (br s, 1H), 3.48(s, 2H), 2.55 (t, J = 4.9 Hz, 2H), 2.48 (br s, 2H), 2.20-2.18 (m, 5H),1.50 (d, J = 7.0 Hz, 3H), 1.04 (s, 6H), 0.78 (br s, 3H); 49:(R)-3-(2-((S)-1-(4-((4,4- ¹H NMR (400 MHz, MeOD) δ 8.11 (d, HRMS m/zdifluoropiperidin-1-yl)methyl)-3- J = 5.8 Hz, 1H), 7.38-7.30 (m, 2H),480.2204 fluorophenyl)ethylamino)pyrimidin-4- 7.18 (dd, J = 7.9, 1.7 Hz,1H), 7.10 (d, (M + H)⁺. yl)-4-((R)-1-hydroxyethyl)oxazolidin-2- J = 11.3Hz, 1H), 5.08 (q, J = 6.9 Hz, one 1H), 4.80 (br s, 1H), 4.52 (dd, J =9.1, 2.8 Hz, 1H), 4.38 (t, J = 8.9 Hz, 1H), 4.01 (br s, 1H), 3.60 (s,2H), 2.60- 2.58 (m, 4H), 2.05-1.89 (m, 4H), 1.50 (d, J = 7.0 Hz, 3H),0.77 (br s, 3H) 50: (R)-3-(2-(((S)-1-(5-(4-fluoro-3- ¹H NMR (400 MHz,MeOD) δ 8.70 (d, HRMS m/z methylphenyl)pyridin-2- J = 2.5 Hz, 1H), 8.14(s, 1H), 7.97 (dd, 438.1927 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- J =8.2, 2.3 Hz, 1H), 7.55-7.43 (m, (M + H)⁺. hydroxyethyl)oxazolidin-2-one3H), 7.36 (d, J = 5.8 Hz, 1H), 7.13 (dd, J = 9.5, 8.5 Hz, 1H), 5.16 (q,J = 7.0 Hz, 1H), 4.78 (br s, 1H), 4.51 (dd, J = 9.3, 2.7 Hz, 1H), 4.37(t, J = 8.9 Hz, 1H), 3.67 (br s, 1H), 2.33 (d, J = 1.9 Hz, 3H), 1.59 (d,J = 7.1 Hz, 3H), 0.68 (br s, 3H); 51: (R)-4-((R)-1-hydroxyethyl)-3-(2-¹H NMR (400 MHz, MeOD) δ 8.79 (d, HRMS m/z (((S)-1-(5-(3- J = 2.5 Hz,1H), 8.14 (s, 1H), 8.06 (dd, 474.1739 (trifluoromethyl)phenyl)pyridin-2-J = 8.3, 2.4 Hz, 1H), 7.95-7.89 (m, (M + H)⁺.yl)ethyl)amino)pyrimidin-4- 2H), 7.74-7.64 (m, 2H), 7.55 (d, J =yl)oxazolidin-2-one 8.2 Hz, 1H), 7.36 (d, J = 5.7 Hz, 1H), 5.18 (q, J =7.0 Hz, 1H), 4.79 (s, 1H), 4.51 (dd, J = 9.1, 2.7 Hz, 1H), 4.37 (t, J =8.9 Hz, 1H), 3.63 (br s, 1H), 1.60 (d, J = 7.0 Hz, 3H), 0.68 (br s, 3H);52: (R)-3-(2-(((S)-1-(6-(4-fluoro-3- ¹H NMR (400 MHz, MeOD) δ 8.60 (d,HRMS m/z methylphenyl)pyridin-3- J = 2.2 Hz, 1H), 8.13 (d, J = 6.0 Hz,438.1985 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 1H), 7.88 (dd, J =8.3, 2.3 Hz, 1H), (M + H)⁺. hydroxyethyl)oxazolidin-2-one 7.84-7.69 (m,3H), 7.35 (d, J = 5.8 Hz, 1H), 7.12 (t, J = 9.0 Hz, 1H), 5.17 (q, J =7.0 Hz, 1H), 4.83 (br s, 1H), 4.52 (dd, J = 9.3, 2.7 Hz, 1H), 4.39 (t, J= 8.9 Hz, 1H), 3.87 (br s, 1H), 2.33 (d, J = 1.9 Hz, 3H), 1.59 (d, J =7.0 Hz, 3H), 0.76 (br s, 3H); 53: (R)-4-((R)-1-hydroxyethyl)-3-(2- ¹HNMR (400 MHz, MeOD) δ 8.68 (d, HRMS m/z (((S)-1-(6-(3- J = 2.1 Hz, 1H),8.27 (s, 1H), 8.19 (d, 474.1816 (trifluoromethyl)phenyl)pyridin-3- J =7.7 Hz, 1H), 8.14 (d, J = 5.8 Hz, (M + H)⁺. yl)ethyl)amino)pyrimidin-4-1H), 7.98-7.85 (m, 2H), 7.76-7.62 yl)oxazolidin-2-one (m, 2H), 7.35 (d,J = 5.8 Hz, 1H), 5.19 (q, J = 7.0 Hz, 1H), 4.83 (s, 1H), 4.52 (dd, J =9.1, 2.7 Hz, 1H), 4.39 (t, J = 8.9 Hz, 1H), 3.84 (br s, 1H), 1.60 (d, J= 7.1 Hz, 3H), 0.75 (br s, 3H); 54: (R)-3-(2-(((S)-1-(5-(4-fluoro-3- ¹HNMR (400 MHz, MeOD) δ 9.00 (d, HRMS m/z methylphenyl)pyrazin-2- J = 1.5Hz, 1H), 8.65 (d, J = 1.5 Hz, 439.1872yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 1H), 8.15 (d, J = 5.9 Hz, 1H),7.94 (M + H)⁺. hydroxyethyl)oxazolidin-2-one (ddd, J = 7.3, 2.3, 0.9 Hz,1H), 7.87 (ddd, J = 7.7, 4.9, 2.4 Hz, 1H), 7.38 (d, J = 5.8 Hz, 1H),7.16 (dd, J = 9.5, 8.6 Hz, 1H), 5.25 (q, J = 7.0 Hz, 1H), 4.82 (br s,1H), 4.51 (dd, J = 9.3, 2.8 Hz, 1H), 4.38 (t, J = 8.9 Hz, 1H), 3.84 (brs, 1H), 2.35 (d, J = 1.8 Hz, 3H), 1.63 (d, J = 7.1 Hz, 3H), 0.80 (br s,3H); 55: (R)-4-((R)-1-hydroxyethyl)-3-(2- 1H NMR (400 MHz, MeOD) δ 8.95(d, HRMS m/z (((S)-1-(2′-(trifluoromethyl)-[3,4′- J = 2.3 Hz, 1H), 8.79(d, J = 5.1 Hz, 475.1685 bipyridin]-6-yl)ethyl)amino)pyrimidin-4- 1H),8.22 (dd, J = 8.3, 2.4 Hz, 1H), (M + H)⁺. yl)oxazolidin-2-one 8.19-8.11(m, 2H), 7.99 (dd, J = 5.1, 1.7 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.37(d, J = 5.8 Hz, 1H), 5.19 (q, J = 7.0 Hz, 1H), 4.78 (s, 1H), 4.55-4.45(m, 1H), 4.37 (t, J = 8.9 Hz, 1H), 3.73- 3.44 (m, 1H), 1.60 (d, J = 7.0Hz, 3H), 0.69 (br s, 3H); 56: (R)-4-((R)-1-hydroxyethyl)-3-(2- ¹H NMR(400 MHz, MeOD) δ 9.30 (d, HRMS m/z (((S)-1-(6′-(trifluoromethyl)-[2,3′-J = 2.0 Hz, 1H), 8.75 (s, 1H), 8.60 (dd, 475.1689bipyridin]-5-yl)ethyl)amino)pyrimidin-4- J = 8.2, 2.1 Hz, 1H), 8.14 (d,J = 5.8 (M + H)⁺. yl)oxazolidin-2-one Hz, 5H), 7.98 (t, J = 1.4 Hz, 2H),7.93 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 5.8 Hz, 1H), 5.20 (q, J = 7.0 Hz,1H), 4.83 (br s, 1H), 4.52 (dd, J = 9.2, 2.7 Hz, 1H), 4.39 (t, J = 8.9Hz, 1H), 3.80 (br s, 1H), 1.61 (d, J = 7.0 Hz, 3H), 0.75 (br s, 3H); 57:(R)-4-((R)-1-hydroxyethyl)-3-(2- ¹H NMR (400 MHz, MeOD) δ 9.03 (d, HRMSm/z (((S)-1-(6′-(trifluoromethyl)-[3,3′- J = 2.2 Hz, 1H), 8.88 (d, J =1.8 Hz, 475.1689 bipyridin]-6-yl)ethyl)amino)pyrimidin-4- 1H), 8.34 (dd,J = 8.3, 2.2 Hz, 1H), (M + H)⁺. yl)oxazolidin-2-one 8.15 (dd, J = 8.1,2.5 Hz, 2H), 7.93 (d, J = 8.4 Hz, 1H), 7.63-7.58 (m, 1H), 7.37 (d, J =5.8 Hz, 1H), 5.19 (q, J = 7.1 Hz, 1H), 4.79 (br s, 1H), 4.51 (dd, J =9.1, 2.7 Hz, 1H), 4.38 (t, J = 8.9 Hz, 1H), 3.71-3.47 (m, 1H), 1.61 (d,J = 7.1 Hz, 3H), 0.70 (br s, 3H); 58: (R)-4-((R)-1-hydroxyethyl)-3-(2-¹H NMR (400 MHz, MeOD) δ 9.24- HRMS m/z(((S)-1-(6-(trifluoromethyl)-[2,3′- 9.19 (m, 1H), 8.47 (dd, J = 8.3, 2.3475.1721 bipyridin]-6′-yl)ethyl)amino)pyrimidin- Hz, 1H), 8.24-8.07 (m,3H), 7.79 (dd, (M + H)⁺. 4-yl)oxazolidin-2-one J = 7.7, 0.9 Hz, 1H),7.60 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 5.9 Hz, 1H), 5.21 (q, J = 7.0 Hz,1H), 4.80 (br s, 1H), 4.58-4.44 (m, 1H), 4.38 (t, J = 8.8 Hz, 1H), 3.69(br s, 1H), 1.61 (d, J = 7.1 Hz, 3H), 0.69 (br s, 3H); 59:(R)-4-((R)-1-hydroxyethyl)-3-(2- ¹H NMR (400 MHz, MeOD) δ 8.81 (d, HRMSm/z (((S)-1-(4-methyl-2′-(trifluoromethyl)- J = 5.0 Hz, 1H), 8.38 (s,1H), 8.15 (d, 489.1881 [3,4′-bipyridin]-6- J = 5.1 Hz, 1H), 7.90 (s,1H), 7.72 (dd, (M + H)⁺. yl)ethyl)amino)pyrimidin-4- J = 5.0, 1.6 Hz,1H), 7.45 (s, 1H), 7.37 yl)oxazolidin-2-one (d, J = 5.8 Hz, 1H), 5.14(q, J = 7.0 Hz, 1H), 4.79 (br s, 1H), 4.52 (dd, J = 9.3, 2.7 Hz, 1H),4.38 (t, J = 8.9 Hz, 1H), 3.65 (br s, 1H), 2.32 (s, 3H), 1.58 (d, J =7.1 Hz, 3H), 0.77 (br s, 3H); 60: (R)-3-(2-(((S)-1-(5-fluoro-2′- ¹H NMR(400 MHz, MeOD) δ 8.82- HRMS m/z (trifluoromethyl)-[3,4′-bipyridin]-6-8.80 (m, 2H), 8.19 (d, J = 1.5 Hz, 1H), 493.1575yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 8.14 (d, J = 5.8 Hz, 1H), 8.10(dd, J = (M + H)⁺. hydroxyethyl)oxazolidin-2-one 10.8, 1.9 Hz, 1H), 8.00(dd, J = 5.2, 1.7 Hz, 1H), 7.38 (d, J = 5.8 Hz, 1H), 5.54 (q, J = 6.9Hz, 1H), 4.64 (s, 1H), 4.55 (dd, J = 9.3, 2.7 Hz, 1H), 4.41 (t, J = 8.8Hz, 1H), 3.93 (br s, 1H), 1.60 (d, J = 6.9 Hz, 3H) 0.87 (br s, 3H); 61:(R)-4-((R)-1-hydroxyethyl)-3-(2- ¹H NMR (400 MHz, MeOD) δ 8.79 (s, HRMSm/z (((S)-1-(5-methyl-2′-(trifluoromethyl)- 1H), 8.78 (d, J = 4.6 Hz,1H), 8.15 (s, 489.1829 [3,4′-bipyridin]-6- 1H), 8.14 (d, J = 6.3 Hz,1H), 8.05 (s, (M + H)⁺. yl)ethyl)amino)pyrimidin-4- 1H), 7.98 (d, J =5.0 Hz, 1H), 7.37 (d, yl)oxazolidin-2-one J = 5.8 Hz, 0H), 5.49-5.38 (m,1H), 4.90-4.84 (m, 1H), 4.55 (dd, J = 9.2, 2.6 Hz, 1H), 4.41 (t, J = 8.8Hz, 1H), 3.96 (br s, 1H), 2.57 (s, 3H), 1.53 (d, J = 6.7 Hz, 3H), 0.87(br s, 3H); 62: (R)-4-((R)-1-hydroxyethyl)-3-(2- ¹H NMR (400 MHz, MeOD)δ 8.79 (d, HRMS m/z (((S)-1-(2-methyl-2′-(trifluoromethyl)- J = 5.0 Hz,1H), 8.15 (d, J = 5.9 Hz, 489.1840 [3,4′-bipyridin]-6- 1H), 7.88 (s,1H), 7.74-7.65 (m, 2H), (M + H)⁺. yl)ethyl)amino)pyrimidin-4- 7.39 (d, J= 8.0 Hz, 1H), 7.37 (d, J = yl)oxazolidin-2-one 5.8 Hz, 1H), 5.14 (t, J= 7.1 Hz, 1H), 4.79 (br s, 1H), 4.52 (dd, J = 9.3, 2.7 Hz, 1H), 4.38 (t,J = 8.9 Hz, 1H), 3.61 (br s, 1H), 2.53 (s, 3H), 1.59 (d, J = 7.0 Hz,3H), 0.76 (br s, 3H); 63: (R)-3-(2-(((S)-1-(2′-(tert-butyl)- 1H NMR (400MHz, MeOD) δ 8.85 (d, HRMS m/z [3,4′-bipyridin]-6- J = 1.8 Hz, 1H), 8.56(dd, J = 5.3, 0.8 463.2439 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- Hz,1H), 8.16-8.08 (m, 1H), 7.73 (d, (M + H)+. hydroxyethyl)oxazolidin-2-oneJ = 0.7 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.54 (dd, J = 5.2, 1.7 Hz,1H), 7.36 (d, J = 5.8 Hz, 1H), 5.18 (q, J = 7.0 Hz, 1H), 4.78 (br s,1H), 4.56- 4.46 (m, 1H), 4.37 (t, J = 8.8 Hz, 1H), 3.59 (br s, 1H), 1.60(d, J = 7.1 Hz, 3H), 1.42 (s, 9H), 0.67 (br s, 3H); 64:(R)-4-((R)-1-hydroxyethyl)-3-(2- ¹H NMR (400 MHz, MeOD) δ 8.84 (d, HRMSm/z (((S)-1-(2′-(1,1,1-trifluoro-2- J = 2.2 Hz, 1H), 8.64 (d, J = 5.1Hz, 517.2167 methylpropan-2-yl)-[3,4′-bipyridin]-6- 1H), 8.16-8.03 (m,2H), 7.86 (s, 1H), (M + H)⁺. yl)ethyl)amino)pyrimidin-4- 7.64 (dd, J =5.1, 1.6 Hz, 1H), 7.58 (d, yl)oxazolidin-2-one J = 8.2 Hz, 1H), 7.35 (d,J = 5.8 Hz, 1H), 5.18 (q, J = 7.0 Hz, 1H), 4.78 (br s, 1H), 4.50 (dd, J= 9.3, 2.7 Hz, 1H), 4.37 (t, J = 8.8 Hz, 1H), 3.57 (br s, 1H), 1.68 (s,6H), 1.60 (d, J = 7.1 Hz, 3H), 0.67 (br s, 3H); 65:4-(2-((S)-1-((4-((R)-4-((R)-1- ¹H NMR (400 MHz, MeOD) δ 8.19 (d, HRMSm/z hydroxyethyl)-2-oxooxazolidin-3- J = 5.8 Hz, 1H), 8.15-8.09 (m, 2H),437.1375 yl)pyrimidin-2-yl)amino)ethyl)thiazol-4- 7.90 (s, 1H),7.80-7.74 (m, 2H), 7.43 (M + H)⁺. yl)benzonitrile (d, J = 5.8 Hz, 1H),5.51 (q, J = 7.5 Hz, 1H), 4.82 (br s, 1H), 4.49 (dd, J = 9.0, 3.1 Hz,1H), 4.38 (t, J = 8.9 Hz, 1H), 4.10 (br s, 1H), 1.73 (d, J = 7.1 Hz,3H), 0.78 (br s, 3H); 66: (R)-3-(2-(((S)-1-(5-(4- ¹H NMR (400 MHz, MeOD)δ 8.16 (d, HRMS m/z chlorophenyl)isoxazol-3- J = 5.8 Hz, 1H), 7.82-7.76(m, 2H), 430.1260 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 7.53-7.47 (m,2H), 7.40 (d, J = 5.8 (M + H)⁺. hydroxyethyl)oxazolidin-2-one Hz, 1H),6.78 (s, 1H), 5.34 (q, J = 7.1 Hz, 1H), 4.87 (ddd, J = 8.4, 4.2, 2.7 Hz,1H), 4.54 (dd, J = 9.2, 2.7 Hz, 1H), 4.41 (t, J = 8.9 Hz, 1H), 4.31 (brs, 1H), 1.63 (d, J = 7.0 Hz, 3H), 0.93 (br s, 3H); 67:(R)-3-(2-(((R)-1-(4-(2,4- ¹H NMR (400 MHz, MeOD) δ 8.18 (d, HRMS m/zdichlorophenyl)thiazol-2- J = 5.8 Hz, 1H), 7.86 (d, J = 8.4 Hz, 480.0639yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 1H), 7.78 (s, 1H), 7.58 (d, J =2.2 Hz, (M + H)⁺. hydroxyethyl)oxazolidin-2-one 1H), 7.44-7.39 (m, 2H),5.43 (q, J = 7.0 Hz, 1H), 4.64 (br s, 1H), 4.56- 4.49 (m, 2H), 4.30 (brs, 1H), 1.71 (d, J = 7.0 Hz, 3H), 1.06 (d, J = 6.5 Hz, 3H); 68:(R)-3-(2-(((S)-1-(4-(2,4- ¹H NMR (400 MHz, MeOD) δ 8.19 (d, HRMS m/zdichlorophenyl)thiazol-2- J = 5.8 Hz, 1H), 7.91 (d, J = 8.5 Hz, 480.0637yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 1H), 7.81 (s, 1H), 7.58 (d, J =2.1 Hz, (M + H)⁺. hydroxyethyl)oxazolidin-2-one 1H), 7.46-7.39 (m, 2H),5.50 (q, J = 7.0 Hz, 1H), 4.82 (br s, 1H), 4.51 (dd, J = 9.0, 2.7 Hz,1H), 4.38 (t, J = 8.9 Hz, 1H), 4.04 (br s, 1H), 1.72 (d, J = 7.0 Hz,3H), 0.82 (br s, 3H); 69: (R)-3-(2-(((R)-1-(4-(4- ¹H NMR (400 MHz, MeOD)δ 8.17 (d, HRMS m/z bromophenyl)thiazol-2- J = 5.8 Hz, 1H), 7.86-7.81(m, 2H), 490.0533 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 7.69 (s, 1H),7.59-7.54 (m, 2H), 7.42 (M + H)⁺. hydroxyethyl)oxazolidin-2-one (d, J =5.8 Hz, 1H), 5.44 (q, J = 7.0 Hz, 1H), 4.69 (br s, 1H), 4.52 (ddt, J =19.3, 9.1, 4.6 Hz, 2H), 4.26 (br s, 1H), 1.71 (d, J = 7.0 Hz, 3H), 1.08(d, J = 6.5 Hz, 3H); 70: (R)-3-(2-(((S)-1-(4-(4- ¹H NMR (400 MHz, MeOD)δ 8.21 (d, HRMS m/z bromophenyl)thiazol-2- J = 5.8 Hz, 1H), 7.89-7.84(m, 2H), 490.0533 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 7.71 (s, 1H),7.61-7.56 (m, 2H), 7.44 (M + H)⁺. hydroxyethyl)oxazolidin-2-one (d, J =5.8 Hz, 1H), 5.52 (t, J = 3.5 Hz, 1H), 4.84 (br s, 1H), 4.52 (dd, J =9.4, 2.8 Hz, 1H), 4.40 (t, J = 8.9 Hz, 1H), 4.13 (br s, 1H), 1.74 (d, J= 7.0 Hz, 3H), 0.81 (br s, 3H); 71: 4-(2-((R)-1-((4-((R)-4-((R)-1- ¹HNMR (400 MHz, MeOD) δ 8.17 (d, HRMS m/z hydroxyethyl)-2-oxooxazolidin-3-J = 5.8 Hz, 1H), 8.14-8.09 (m, 2H), 437.1382yl)pyrimidin-2-yl)amino)ethyl)thiazol-4- 7.91 (s, 1H), 7.80-7.74 (m,2H), 7.42 (M + H)⁺. yl)benzonitrile (d, J = 5.8 Hz, 1H), 5.46 (q, J =7.0 Hz, 1H), 4.70 (br s, 1H), 4.59-4.45 (m, 2H), 4.27 (br s, 1H), 1.73(d, J = 7.0 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H); 72:(R)-4-((R)-1-hydroxyethyl)-3-(2- ¹H NMR (400 MHz, MeOD) δ 8.12 (d, HRMSm/z ((S)-1-(4-((4-methylpiperazin-1- J = 5.8 Hz, 1H), 7.41-7.22 (m, 5H),441.2593 yl)methyl)phenyl)ethylamino)pyrimidin- 5.09 (q, J = 7.0 Hz,1H), 4.53 (dd, J = (M + H)⁺. 4-yl)oxazolidin-2-one 9.3, 2.8 Hz, 1H),4.39 (t, J = 8.9 Hz, 1H), 3.99 (s, 1H), 3.52 (d, J = 1.5 Hz, 2H), 2.56(bs, 8H), 2.28 (s, 3H), 1.52 (d, J = 7.0 Hz, 3H), 0.78 (s, 3H). 73:(4R)-3-(2-((1-(3-fluoro-4-(4- ¹H NMR (400 MHz, MeOD) δ 8.14 (t, HRMS m/zmethyl-1H-pyrazol-1- J = 5.7 Hz, 1H), 7.86-7.77 (m, 1H), 427.1870yl)phenyl)ethyl)amino)pyrimidin-4-yl)- 7.64 (td, J = 8.3, 2.2 Hz, 1H),7.56 (d, (M + H)⁺. 4-((R)-1-hydroxyethyl)oxazolidin-2-one J = 3.0 Hz,1H), 7.42-7.28 (m, 3H), 5.20-4.99 (m, 1H), 4.75-4.47 (m, 2H), 4.37 (dt,J = 17.1, 8.9 Hz, 1H), 2.17 (s, 3H), 1.56 (d, J = 7.1 Hz, 3H), 1.10 (d,J = 6.5 Hz, 1.5H), 0.82 (br s, 1.5H). 74: (4R)-3-(2-((1-(5-(3,4- ¹H NMR(400 MHz, MeOD) δ 8.27 (d, HRMS m/z dichlorophenyl)-1H-imidazol-2- J =3.1 Hz, 1H), 7.63 (d, J = 5.0 Hz, 481.0930yl)ethyl)amino)-5-fluoropyrimidin-4-yl)- 1H), 7.50 (dd, J = 8.4, 1.6 Hz,1H), (M + H)⁺. 4-((R)-1-hydroxyethyl)oxazolidin-2-one 7.41 (s, 1H), 5.14(q, J = 7.0 Hz, 1H), 4.72 (td, J = 7.1, 5.1 Hz, 1H), 4.56- 4.42 (m, 2H),4.16 (qd, J = 6.4, 5.1 Hz, 1H), 1.63 (dd, J = 10.1, 7.1 Hz, 3H), 1.11(d, J = 6.5 Hz, 3H). 75: (4R)-3-(2-((1-(5-(3,4- ¹H NMR (400 MHz, MeOD) δ8.19 (d, HRMS m/z dichlorophenyl)-1H-imidazol-2- J = 5.8 Hz, 1H), 7.91(s, 1H), 7.63 (s, 463.1018 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 1H),7.50 (d, J = 8.4 Hz, 1H), 7.41 (d, (M H)⁺ hydroxyethyl)oxazolidin-2-oneJ = 5.8 Hz, 1H), 5.27-5.12 (m, 1H), 4.67 (s, 1H), 4.62-4.47 (m, 2H),4.26 (s, 1H), 1.65 (d, J = 7.1 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H). 76:(R)-3-(2-(((S)-1-(5-((4,4- ¹H NMR (400 MHz, MeOD) δ 8.47 (d, HRMS m/zdifluoropiperidin-1-yl)methyl)pyridin-2- J = 2.0 Hz, 1H), 8.15 (d, J =5.9 Hz, 463.2250 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 1H), 7.78 (dd,J = 8.0, 2.2 Hz, 1H), (M + H)⁺. hydroxyethyl)oxazolidin-2-one 7.45 (d, J= 8.1 Hz, 1H), 7.37 (d, J = 5.7 Hz, 1H), 5.26-5.08 (m, 1H), 4.81 (d, J =6.4 Hz, 1H), 4.53 (dd, J = 9.1, 2.7 Hz, 1H), 4.39 (t, J = 8.9 Hz, 1H),3.95-3.64 (m, 1H), 3.61 (s, 2H), 2.59 (t, J = 5.6 Hz, 4H), 1.99 (tt, J =13.7, 5.6 Hz, 4H), 1.56 (d, J = 7.0 Hz, 3H), 0.77 (s, 3H). 77:(R)-3-(2-(((S)-1-(6-((4,4- ¹H NMR (400 MHz, MeOD) δ 8.52 (d, HRMS m/zdifluoropiperidin-1-yl)methyl)pyridin-3- J = 2.3 Hz, 1H), 8.14 (d, J =5.9 Hz, 463.2267 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 1H), 7.85 (dd,J = 8.1, 2.3 Hz, 1H), (M + H)⁺. hydroxyethyl)oxazolidin-2-one 7.51 (d, J= 8.0 Hz, 1H), 7.36 (d, J = 5.8 Hz, 1H), 5.16 (q, J = 7.1 Hz, 1H), 4.83(d, J = 4.5 Hz, 1H), 4.54 (dd, J = 9.3, 2.7 Hz, 1H), 4.40 (t, J = 8.9Hz, 1H), 4.16-3.76 (br s, 1H), 3.69 (s, 2H), 2.61 (t, J = 5.7 Hz, 4H),1.99 (tt, J = 13.5, 5.6 Hz, 4H), 1.57 (d, J = 7.0 Hz, 3H), 0.83 (s, 3H).78: (R)-4-((R)-1-hydroxyethyl)-3-(2- ¹H NMR (400 MHz, MeOD) δ 9.13 (d,HRMS m/z (((R)-1-(5-(3- J = 1.5 Hz, 1H), 8.79 (d, J = 1.5 Hz, 475.1685(trifluoromethyl)phenyl)pyrazin-2- 1H), 8.40 (s, 1H), 8.33 (d, J = 7.8Hz, (M + H)⁺. yl)ethyl)amino)pyrimidin-4- 1H), 8.15 (d, J = 5.8 Hz, 1H),7.78 (d, yl)oxazolidin-2-one J = 7.9 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H),7.38 (d, J = 5.8 Hz, 1H), 5.25 (q, J = 7.0 Hz, 1H), 4.59-4.51 (m, 2H),4.33 (br s, 1H), 1.64 (d, J = 7.0 Hz, 3H), 1.09 (d, J = 6.5 Hz, 3H); 79:(R)-3-(2-(((R)-1-(5-(4-fluoro-3- ¹H NMR (400 MHz, MeOD) δ 8.99 (d, HRMSm/z methylphenyl)pyrazin-2- J = 1.5 Hz, 1H), 8.70 (d, J = 1.6 Hz,439.1869 yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 1H), 8.14 (d, J = 5.8Hz, 1H), 7.99- (M + H)⁺. hydroxyethyl)oxazolidin-2-one 7.92 (m, 1H),7.88 (ddd, J = 8.4, 4.9, 2.4 Hz, 1H), 7.37 (d, J = 5.8 Hz, 1H), 7.16(dd, J = 9.5, 8.6 Hz, 1H), 5.22 (q, J = 7.0 Hz, 1H), 4.64 (br s, 1H),4.60- 4.51 (m, 2H), 4.32 (t, J = 8.7 Hz, 1H), 2.35 (d, J = 2.0 Hz, 3H),1.62 (d, J = 7.0 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H);

The compounds in Table 29a were prepared using methods similar to thosedescribed for the preparation of Examples 35, 36, or 37/38.

TABLE 29a

80 and 81

82 and 83

84 and 85

86 and 87

88 and 89

90 and 91

92 and 93

94 and 95

96 and 97

98 and 99

100 and 101

102 and 103

104 and 105

106 and 107

108 and 109

110 and 111

112 and 113

114 and 115

116 and 117

118 and 119

120 and 121

122 and 123

124 and 125

126 and 127

128 and 129

130 and 131

132 and 133

134 and 135

136 and 137

138 and 139

140 and 141

142 and 143

144 and 145

146 and 147

148 and 149

150 and 151

152 and 153

154 and 155

156 and 157

158 and 159

160 and 161

162 and 163

164 and 165

166 and 167

168 and 169

170 and 171

172 and 173

174 and 175

176 and 177

178 and 179

180 and 181

182 and 183

184 and 185

186 and 187

188 and 189

190 and 191

192 and 193

194 and 195

196 and 197

198 and 199

200 and 201

TABLE 29b Chemical name, NMR chemical shifts, chiral separationconditions and LCMS signal for compounds listed in Table 29a. Chiralseparation conditions, peak identification and Example: Name analyticaldata 80 and 81: Chiral separation was achieved by chiral SFC column(R)-3-(2-((1-(5-(4-fluoro-3- chromatography (Column AD-H 20 × 250 mm 35%IPA 10 mM (trifluoromethyl)phenyl)pyrimidin- NH4OH in CO₂, flow 75g/min, 232 nm UV collection) to 2-yl)ethyl)amino)pyrimidin-4-yl)- give(R)-3-(2-(((S)-1-(5-(4-fluoro-3- 4-((R)-1-hydroxyethyl)oxazolidin-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin- 2-one4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-(5-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one.80: First eluted product (40 mg) ¹H NMR (400 MHz, CDCl₃) δ 8.90 (s, 2H),8.22 (d, J = 5.76 Hz, 1H), 7.83-7.70 (m, 2H), 7.49-7.35 (m, 2H), 6.12(d, J = 8.09 Hz, 1H), 5.40 (p, J = 7.25 Hz, 1H), 4.89 (s, 1H), 4.51 (dd,J = 2.70, 9.45 Hz, 1H), 4.42 (dd, J = 8.23, 9.37 Hz, 1H), 3.30 (s, 1H),1.68 (d, J = 7.25 Hz, 3H), 1.12 (br s, 3H). HRMS(B) m/z 493.1599 (M +H)⁺. 81: Second eluted product (45 mg) ¹H NMR (400 MHz, CDCl₃) δ 8.91(s, 2H), 8.22 (d, J = 5.7 Hz, 1H), 7.84-7.71 (m, 2H), 7.40 (dd, J =11.6, 7.2 Hz, 2H), 6.14 (d, J = 6.8 Hz, 1H), 5.21 (s, 1H), 4.79 (s, 1H),4.58-4.48 (m, 1H), 4.30 (s, 1H), 3.81 (s, 1H), 1.66 (m, 3H), 1.24 (m,3H). HRMS(B) m/z 493.1600 (M + H)⁺. 82 and 83: Chiral separation wasachieved by chiral SFC column (R)-3-(2-((1-(5-(4-chloro-3-chromatography (Column AD-H 20 × 250 mm 30% IPA 10 mM(trifluoromethyl)phenyl)pyrimidin- NH4OH in CO₂, flow 75 g/min, 232 nmUV collection) to 2-yl)ethyl)amino)pyrimidin-4-yl)- give(R)-3-(2-(((S)-1-(5-(4-chloro-3- 4-((R)-1-hydroxyethyl)oxazolidin-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin- 2-one4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-(5-(4-chloro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one.82: First eluted product (13 mg) ¹H NMR (400 MHz, CDCl₃) δ 8.91 (s, 2H),8.22 (d, J = 5.8 Hz, 1H), 7.90-7.85 (m, 1H), 7.68 (d, J = 1.8 Hz, 2H),7.45 (d, J = 5.7 Hz, 1H), 6.08 (d, J = 8.2 Hz, 1H), 5.40 (q, J = 7.5 Hz,1H), 4.89 (s, 1H), 4.51 (dd, J = 9.4, 2.7 Hz, 1H), 4.42 (dd, J = 9.4,8.3 Hz, 1H), 4.09 (s, 1H), 3.29 (s, 1H), 1.68 (d, J = 7.5 Hz, 3H), 1.12(br s, 3H). HRMS(B) m/z 509.1306 (M + H)⁺. 83: Second eluted product (12mg) ¹H NMR (400 MHz, CDCl₃) δ 8.93 (s, 2H), 8.23 (d, J = 5.7 Hz, 1H),7.88 (d, J = 1.7 Hz, 1H), 7.69 (d, J = 1.4 Hz, 2H), 7.42 (d, J = 5.7 Hz,1H), 6.09 (d, J = 6.8 Hz, 1H), 5.21 (s, 1H), 4.78 (s, 1H), 4.53 (d, J =8.9 Hz, 1H), 4.31 (s, 1H), 3.70 (s, 1H), 1.66 (m, 3H), 1.24 (m, 3H).HRMS(B) m/z 509.1312 (M + H)⁺. 84 and 85: Chiral separation was achievedby chiral SFC column (R)-3-(2-((1-(5-(3,4- chromatography (Column C6AD-H 20 × 250 mm 35% IPA 5 dichlorophenyl)pyrimidin-2- mM NH₄OH in CO₂,flow 80 mL/min, 232 nm UV collection) yl)ethyl)amino)pyrimidin-4-yl)-4-to give (R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one. 84: First eluted product (28 mg)¹H NMR (400 MHz, CDCl₃) δ 8.89 (s, 2H), 8.22 (d, J = 5.7 Hz, 1H),7.70-7.58 (m, 2H), 7.49-7.37 (m, 2H), 6.03 (d, J = 7.5 Hz, 1H), 5.39 (t,J = 7.4 Hz, 1H), 4.89 (s, 1H), 4.55-4.47 (m, 1H), 4.42 (dd, J = 9.4, 8.3Hz, 1H), 3.25 (s, 1H), 1.67 (dd, J = 7.0, 4.3 Hz, 3H), 1.12 (br s, 3H).HRMS(B) m/z 475.1026 (M + H)⁺. 85: Second eluted product (22 mg) ¹H NMR(400 MHz, CDCl₃) δ 8.90 (s, 2H), 8.23 (d, J = 5.7 Hz, 1H), 7.71-7.57 (m,2H), 7.46-7.38 (m, 2H), 6.01 (s, 1H), 5.18 (s, 1H), 4.78 (s, 1H), 4.53(d, J = 9.0 Hz, 1H), 4.31 (s, 2H), 3.64 (s, 1H), 1.66 (d, J = 6.9 Hz,3H), 1.26-1.21 (m, 3H). HRMS(B) m/z 475.1032 (M + H)⁺. 86 and 87: Chiralseparation was achieved by chiral SFC column(R)-4-((R)-1-hydroxyethyl)-3-(2-((1-(5-(3- chromatography (Column AD-H20 × 250 mm 35% IPA 10 mM (trifluoromethyl)phenyl)pyrimidin- NH4OH inCO₂, flow 75 g/min, 232 nm UV collection) to2-yl)ethyl)amino)pyrimidin-4- give(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3- yl)oxazolidin-2-one(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one. 86:: First elutedproduct (80 mg) ¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 2H), 8.23 (d, J = 5.7Hz, 1H), 7.85-7.63 (m, 4H), 7.46 (d, J = 5.7 Hz, 1H), 6.11 (d, J = 8.2Hz, 1H), 5.41 (p, J = 7.2 Hz, 1H), 4.90 (s, 1H), 4.52 (dd, J = 9.5, 2.6Hz, 1H), 4.43 (dd, J = 9.4, 8.3 Hz, 1H), 3.34 (s, 1H), 1.67 (d, J = 7.2Hz, 3H), 1.12 br (s, 3H). HRMS(B) m/z 475.1681 (M + H)⁺. 87: Secondeluted product (67 mg) ¹H NMR (400 MHz, CDCl₃) δ 8.95 (s, 2H), 8.20 (d,J = 5.9 Hz, 1H), 7.86-7.64 (m, 4H), 7.46 (d, J = 5.9 Hz, 1H), 6.48 (brs, 1H), 5.20 (br s, 1H), 4.79 (br s, 1H), 4.55 (d, J = 8.6 Hz, 1H),4.34-4.30 (m, 2H), 3.65 (br s, 1H), 1.67 (d, J = 7.2 Hz, 3H), 1.25 (d, J= 6.5 Hz, 3H). HRMS(B) m/z 475.1677 (M + H)⁺. 88 and 89: Chiralseparation was achieved by chiral SFC column(R)-3-(2-((1-(5-(4-chloro-3- chromatography (Column C6 AD-H 20 × 250 mm35% IPA 5 methylphenyl)pyrimidin-2- mM NH4OH in CO₂, flow 80 mL/min, 232nm UV collection) yl)ethyl)amino)pyrimidin-4-yl)-4- to give(R)-3-(2-(((S)-1-(5-(4-chloro-3- ((R)-1-hydroxyethyl)oxazolidin-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4- 2-one((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-(5-(4-chloro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one.88: First eluted product (16 mg) ¹H NMR (400 MHz, CDCl₃) δ 8.79 (s, 2H),8.13 (d, J = 5.7, 1H), 7.44-7.17 (m, 4H), 6.07-5.96 (m, 1H), 5.29 (t, J= 7.7 Hz, 1H), 5.12 (s, 1H), 4.81 (d, J = 7.3 Hz, 1H), 4.55 (s, 1H),4.43 (dd, J = 9.4, 2.6 Hz, 1H), 3.38 (s, 1H), 2.39 (s, 3H), 1.57 (d, J =7.7 Hz, 3H), 1.02 (br s, 3H). HRMS(B) m/z 455.1575 (M + H)⁺. 89: Secondeluted product (9 mg) ¹H NMR (400 MHz, CDCl₃) δ 8.80 (s, 2H), 8.13 (d, J= 5.7 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.37-7.23 (m, 3H), 5.97 (br s,1H), 5.08 (br s, 1H), 4.71 (br s, 1H), 4.45 (d, J = 9.0 Hz, 1H),4.40-4.18 (m, 2H), 3.86 (br s, 1H), 2.39 (s, 3H), 1.57 (d, J = 7.7 Hz,3H), 1.16-1.13 (m, 3H). HRMS(B) m/z 455.1578 (M + H)⁺. 90 and 91: Chiralseparation was achieved by chiral SFC column(R)-3-(2-((1-(5-(3-chloro-5- chromatography (Column Coated 1 P9: AD-H4.6 × 100 mm (trifluoromethyl)phenyl)pyrimidin- 5-55% IPA 5 mM NH₃ inCO₂, flow 5 mL/min, 177 nm UV 2-yl)ethyl)amino)pyrimidin-4-yl)-collection) to give (R)-3-(2-(((S)-1-(5-(3-chloro-5-4-((R)-1-hydroxyethyl)oxazolidin-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin- 2-one4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-(5-(3-chloro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one.90: First eluted product (4 mg) ¹H NMR (400 MHz, CDCl₃) δ 8.83 (s, 2H),8.14 (d, J = 5.8 Hz, 1H), 7.69-7.57 (m, 3H), 7.37 (d, J = 5.8 Hz, 1H),5.99 (d, J = 7.7 Hz, 1H), 5.32 (p, J = 7.1 Hz, 1H), 4.81 (d, J = 7.5 Hz,1H), 4.42 (dd, J = 9.4, 2.4 Hz, 1H), 4.33 (dd, J = 9.4, 8.3 Hz, 1H),3.18 (br s, 1H), 1.57 (d, J = 9.5 Hz, 3H), 1.03 (br s, 3H). HRMS(B) m/z509.1299 (M + H)⁺. 91: Second eluted product (4 mg) ¹H NMR (400 MHz,CDCl₃) δ 8.83 (s, 2H), 8.13 (d, J = 5.7 Hz, 1H), 7.69-7.58 (m, 3H), 7.34(d, J = 5.7 Hz, 1H), 5.97 (d, J = 7.5 Hz, 1H), 5.35-5.31 (m, 1H), 5.13(br s, 1H), 4.45 (d, J = 9.0 Hz, 1H), 4.35-4.24 (m, 1H), 4.22 (s, 1H),3.62 (br s, 1H), 1.57 (d, J = 7.0 Hz, 3H), 1.19-1.16 (m, 3H). HRMS(B)m/z 509.1298 (M + H)⁺. 92 and 93: Chiral separation was achieved bychiral SFC column (R)-3-(2-((1-(3-(4-chlorophenyl)- chromatography IA, 5UM, 20 × 250 MM column, 74 ml/min, 1,2,4-oxadiazol-5- 60 bar, eluting25% IPA with 5 mM NH4OH/CO2 (v/v) to yl)ethyl)amino)pyrimidin-4-yl)-4-give (R)-3-(2-(((R)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one. 92: First eluted product(12.4 mg). HRMS(B) m/z 431.1225 (M + H)⁺. RT = 2.39 min. 93: Secondeluted product (14.3 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J = 6.0 Hz,1H), 8.10-7.94 (m, 2H), 7.57 (d, J = 5.7 Hz, 1H), 7.53-7.43 (m, 2H),5.96 (b, 1H), 5.38 (s, 1H), 4.84 (ddd, J = 8.3, 4.5, 2.5 Hz, 1H), 4.54(dd, J = 9.4, 2.5 Hz, 1H), 4.40 (dd, J = 9.4, 8.3 Hz, 1H), 4.18-3.59 (b,1H), 1.79 (d, J = 7.1 Hz, 3H), 1.01 (b, 3H). HRMS(B) m/z 431.1219 (M +H)⁺, RT = 2.40 min. 94 and 95: Chiral separation was achieved by chiralSFC column (R)-3-(2-((1-(5-(4-fluorophenyl)- chromatography ID-H, 5 UM,20 × 250 MM column, 80 1,3,4-oxadiazol-2- ml/min, 99 bar, eluting 30%IPA with 5 mM NH4OH/CO2 yl)ethyl)amino)pyrimidin-4-yl)-4- (v/v) to give(R)-3-(2-(((R)-1-(5-(4-fluorophenyl)-1,3,4-((R)-1-hydroxyethyl)oxazolidin-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 2-onehydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one. 94: First eluted product(30.1 mg). HRMS (B) m/z 415.1519 (M + H)⁺. RT = 1.80 min. 95: Secondeluted product (32.3 mg). HRMS(B) m/z 415.1521 (M + H)⁺, RT = 1.79 min.96 and 97: Chiral separation was achieved by chiral SFC column(R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography IA, 5 UM, 20 × 250 MMcolumn, 80 ml/min, ((1-(3-(2-phenoxyethyl)-1,2,4- 99 bar, eluting 20%IPA with 5 mM NH4OH/CO2 (v/v) to oxadiazol-5-give(R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(2-yl)ethyl)amino)pyrimidin-4-phenoxyethyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one yl)oxazolidin-2-one and(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(2-phenoxyethyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one. 96: First eluted product(19.2 mg). HRMS(B) m/z 441.1867 (M + H)⁺. RT = 1.90 min. 97: Secondeluted product (31.2 mg). HRMS(B) m/z 441.1864 (M + H)⁺, RT = 1.94 min.98 and 99: Chiral separation was achieved by chiral SFC column(R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography IA, 5 UM, 20 × 250 MMcolumn, 80 ml/min, ((1-(5-(p-tolyl)-1,3,4-oxadiazol-2- 100 bar, eluting15% IPA with 0.5% NH4OH/CO2 (v/v) to yl)ethyl)amino)pyrimidin-4- give(R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(5-(p-tolyl)-yl)oxazolidin-2-one.1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin- 2-one and(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one. 98: First eluted product (48 mg). HRMS(B) m/z411.1768 (M + H)⁺. RT = 1.82 min. 99: Second eluted product (50 mg).HRMS(B) m/z 411.1768 (M + H)⁺, RT = 1.82 min. 100 and 101: Chiralseparation was achieved by chiral SFC column(R)-3-(2-((1-(3-(4-fluorophenyl)- chromatography IA, 5 UM, 20 × 250 MMcolumn, 80 ml/min, 1,2,4-oxadiazol-5- 100 bar, eluting 15% IPA with 0.5%NH4OH/CO2 (v/v) to yl)ethyl)amino)pyrimidin-4-yl)-4- give(R)-3-(2-(((R)-1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one. 100: First eluted product(40 mg). HRMS(B) m/z 415.1516 (M + H)⁺. RT = 1.96 min. 101: Secondeluted product (13 mg). HRMS(B) m/z 415.1518 (M + H)⁺. RT = 1.97 min.102 and 103: Chiral separation was achieved by chiral SFC column(R)-3-(2-((1-(5-(2-fluorophenyl)- chromatography IA, 5 UM, 20 × 250 MMcolumn, 74 ml/min, 1,3,4-oxadiazol-2- 99 bar, eluting 35% IPA with 5 mMNH4OH/CO2 (v/v) to yl)ethyl)amino)pyrimidin-4-yl)-4- give(R)-3-(2-(((R)-1-(5-(2-fluorophenyl)-1,3,4-oxadiazol-2-((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-2-one. hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(5-(2-fluorophenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one. 102: First eluted product(44 mg). HRMS(B) m/z 415.1514 (M + H)⁺. RT = 1.58 min. 103: Secondeluted product (51 mg). HRMS(B) m/z 415.1510 (M + H)⁺. RT = 1.58 min.104 and 105: Chiral separation was achieved by chiral SFC column(R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography IA, 5 UM, 20 × 250 MMcolumn, 74 ml/min, ((1-(5-(m-tolyl)-1,3,4-oxadiazol- 99 bar, eluting 35%IPA with 5 mM NH4OH/CO2 (v/v) to 2-yl)ethyl)amino)pyrimidin-4- give(R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(5-(m-tolyl)-yl)oxazolidin-2-one1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin- 2-one and(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(m-tolyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one. 104: First eluted product (42 mg). HRMS(B) m/z411.1762 (M + H)⁺. RT = 1.78 min. 105: Second eluted product (51 mg).HRMS(B) m/z 411.1762 (M + H)⁺. RT = 1.82 min. 106 and 107: Chiralseparation was achieved by chiral SFC column(R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography IA, 5 UM, 20 × 250 MMcolumn, 74 ml/min, ((1-(5-(o-tolyl)-1,3,4-oxadiazol-2- 99 bar, eluting35% IPA with 5 mM NH4OH/CO2 (v/v) to yl)ethyl)amino)pyrimidin-4- give(R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(5-(o-tolyl)-yl)oxazolidin-2-one1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin- 2-one and(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(o-tolyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one. 106: First eluted product (44 mg). HRMS(B) m/z411.1766 (M + H)⁺. RT = 1.80 min. 107: Second eluted product (42 mg).HRMS(B) m/z 411.1764 (M + H)⁺. RT = 1.80 min. 108 and 109: Chiralseparation was achieved by chiral SFC column(R)-3-(2-((1-(4-(4-chlorophenyl)- chromatography ID, 5 UM, 20 × 250 MMcolumn, 89 ml/min, 5-methylthiazol-2- 99 bar, eluting 22% MeOH/CO2 (v/v)to give (R)-3-(2-(((R)- yl)ethyl)amino)pyrimidin-4-yl)-4-1-(4-(4-chlorophenyl)-5-methylthiazol-2- ((R)-1-hydroxyethyl)oxazolidin-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 2-onehydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(4-(4-chlorophenyl)-5-methylthiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one. 108: First eluted product(44 mg). HRMS(B) m/z 411.1766 (M + H)⁺. RT = 1.80 min. 109: Secondeluted product (34 mg). HRMS(B) m/z 460.1198 (M + H)⁺. RT = 2.41 min.110 and 111: Chiral separation was achieved by chiral SFC column(R)-3-(2-{1-[5-(3-fluoro-phenyl)- chromatography IA, 5 UM, 20 × 250 MMcolumn, 80 ml/min, [1,3,4]oxadiazol-2-yl]- eluting 20% IPA with 5 mMNH4OH/CO2 (v/v) to give (R)-3- ethylamino}-pyrimidin-4-yl)-4-(2-{(R)-1-[5-(3-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-((R)-1-hydroxy-ethyl)-oxazolidin-ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)- 2-one.oxazolidin-2-one and (R)-3-(2-{(S)-1-[5-(3-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one. 110: First eluted product (34.1 mg).HRMS(B) m/z 415.1510 (M + H)⁺. RT = 1.70 min. 111: Second eluted product(41.9 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 7.82 (dt, J = 7.7,1.2 Hz, 1H), 7.72 (ddd, J = 9.1, 2.6, 1.6 Hz, 1H), 7.64-7.42 (m, 2H),7.35- 7.17 (m, 1H), 6.21 (s, 1H), 5.57-5.35 (m, 1H), 4.93 (dt, J = 6.7,2.9 Hz, 1H), 4.61 (dd, J = 9.5, 2.4 Hz, 2H), 4.42 (dd, J = 9.3, 8.3 Hz,2H), 3.98 (s, 1H), 1.08 (d, J = 6.4 Hz, 3H), 0.92-0.77 (m, 3H). HRMS(B)m/z 415.1515 (M +H)⁺, RT = 1.70 min. 112 and 113: Chiral separation wasachieved by chiral SFC column (R)-4-((R)-1-Hydroxy-ethyl)-3-{2-chromatography AD-H 20 × 250 mm, 20% MeOH in CO₂, [1-(5-pyridin-3-yl- 80g/min, UV220 nm to give (R)-4-((R)-1-Hydroxy-ethyl)-3-[1,3,4]oxadiazol-2-yl)-{2-[(R)-1-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-ethylamino]-ethylamino]-pyrimidin-4-yl}- pyrimidin-4-yl}-oxazolidin-2-one and(R)-4-((R)-1-Hydroxy- oxazolidin-2-oneethyl)-3-{2-[(S)-1-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-ethylamino]-pyrimidin-4-yl}-oxazolidin-2-one. 112: First eluted product(39.9 mg). HRMS(B) m/z 398.1566 (M + H)⁺. RT = 1.18 min. 113: Secondeluted product (40.2 mg). ¹H NMR (400 MHz, CDCl₃) δ 9.26 (s, 1H), 8.80(s, 1H), 8.33 (d, J = 7.9 Hz, 1H), 8.23 (s, 1H), 7.54 (d, J = 5.3 Hz,1H), 7.48 (dd, J = 8.2, 4.6 Hz, 1H), 6.17 (s, 1H), 5.46 (s, 1H),4.99-4.84 (m, 1H), 4.60 (dd, J = 9.3, 2.3 Hz, 2H), 4.42 (dd, J = 9.3,8.3 Hz, 2H), 4.01 (s, 1H), 1.09 (d, J = 6.5 Hz, 3H), 0.91-0.81 (m, 3H).HRMS(B) m/z 398.1660, (M + H)⁺. RT = 1.17 min. 114 and 115: Chiralseparation was achieved by chiral SFC column (R)-3-{2-[1-(5-Benzyl-chromatography AD-H 21 × 250 mm, 25% MeOH in CO₂,[1,2,4]oxadiazol-3-yl)- 75 g/min, UV224 nm to give(R)-3-{2-[(R)-1-(5-Benzyl- ethylamino]-pyrimidin-4-yl}-4-[1,2,4]oxadiazol-3-yl)-ethylamino]-pyrimidin-4-yl}-4-((R)-1-((R)-1-hydroxy-ethyl)-oxazolidin- hydroxy-ethyl)-oxazolidin-2-one and(R)-3-{2-[(S)-1-(5- 2-oneBenzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]-pyrimidin-4-yl}-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one. 114: First eluted product (48.9mg). HRMS(B) m/z 411.1855 (M + H)⁺. RT = 1.85 min. 115: Second elutedproduct (52.2 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J = 5.7 Hz, 1H),7.38 (d, J = 5.8 Hz, 1H) 7.31-7.13 (m, 5H), 6.09 (s, 1H), 5.21 (dq, J =14.4, 7.1 Hz, 1H), 4.90-4.69 (m, 1H), 4.42 (dd, J = 9.4, 2.5 Hz, 1H),4.33-4.20 (m, 1H), 4.12 (s, 2H), 3.99 (d, J = 24.4 Hz, 1H), 1.54 (d, J =7.1 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H). HRMS(B) m/z 411.1864, (M + H)⁺.RT = 1.86 min. 116 and 117: Chiral separation was achieved by chiral SFCcolumn (R)-3-{2-[1-(5-Benzyl- chromatography AD-H 21 × 250 mm, 25% MeOHin CO₂, [1,2,4]oxadiazol-3-yl)- 75 g/min, UV231 nm to give(R)-3-{2-[(R)-1-(5-Benzyl- ethylamino]-5-fluoro-pyrimidin-4-[1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-4-y|}-4-((R)-1-hydroxy-ethyl)- ((R)-1-hydroxy-ethyl)-oxazolidin-2-one and(R)-3-{2-[(S)-1- oxazolidin-2-one(5-Benzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one. 116: Firsteluted product (29.4 mg). HRMS(B) m/z429.1667 (M + H)⁺. RT = 1.84 min.117: Second eluted product (52.2 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.14 (d,J = 2.8 Hz, 1H), 7.38-7.13 (m, 5H), 5.64 (d, J = 8.3 Hz, 1H), 5.25-5.08(m, 1H), 4.66 (s, 1H), 4.44 (t, J = 9.0 Hz, 1H), 4.28 (dd, J = 9.1, 5.8Hz, 1H), 4.12 (s, 2H), 3.84 (s, 1H), 1.58-1.50 (m, 3H), 0.99 (d, J = 6.4Hz, 3H). HRMS(B) m/z 429.1671, (M + H)⁺. RT = 1.84 min. 118 and 119:Chiral separation was achieved by chiral SFC column(4R)-3-{2-[1-(3-(4-bromophenyl)- chromatography AD-H 21 × 250 mm, 25%IPA in CO₂, 1,2,4-oxadiazol-5-yl)ethyl]amino}- 75 g/min, UV240 nm togive (R)-3-{2-[(R)1-(3-(4- pyrimidin-4-yl}-4-((R)-1-bromophenyl)-1,2,4-oxadiazol-5-yl)ethyl]amino}-pyrimidin-hydroxyethyl)-oxazolidin-2-one4-yl}-4-((S)-1-hydroxyethyl)-oxazolidin-2-one and (R)-3-{2-[1-(3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl)ethyl]amino}-pyrimidin-4-yl}-4-((R)-1-hydroxyethyl)-oxazolidin-2-one 118: Firsteluted product (34.3 mg). HRMS(B) m/z 477.0856 (M + H)⁺. RT = 2.31 min.119: Second eluted product (33.5 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d,J = 5.8 Hz, 1H), 8.04-7.81 (m, 2H), 7.76- 7.58 (m, 2H), 7.55 (d, J = 5.8Hz, 1H), 5.38 (s, 1H), 4.84 (ddd, J = 8.3, 4.5, 2.5 Hz, 1H), 4.54 (dd, J= 9.4, 2.5 Hz, 1H), 4.39 (dd, J = 9.4, 8.3 Hz, 1H), 3.92 (s, 1H), 1.78(d, J = 7.1 Hz, 3H), 1.01 (d, J = 7.2 Hz, 3H). HRMS(B) m/z 477.0856 (M +H)⁺. RT = 2.32 min. 120 and 121: Chiral separation was achieved bychiral SFC column (4R)-3-{2-[(1-(3-(3-fluoro-4- chromatography OJ-H 21 ×250 mm, 15% MeOH in CO₂, methylphenyl)-1,2,4-oxadiazol-5- 80 g/min,UV233 nm to give (R)-3-{2-[((R)1-(3-(3-fluoro-4-yl)-ethyl]amino}pyrimidin-4-yl}-4-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl]amino}pyrimidin-4-((R)-1-hydroxyethyl)oxazolidin-yl}-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-{2- 2-one[(1(S)-(3-(3-fluoro-4-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl]amino}pyrimidin-4-yl}-4-((R)-1- hydroxyethyl)oxazolidin-2-one120: First eluted product (40.1 mg). HRMS(B) m/z 429.1785 (M + H)⁺. RT =2.23 min. 121: Second eluted product (42.9 mg). ¹H NMR (400 MHz, CDCl₃)δ 8.25 (d, J = 5.8 Hz, 1H), 7.87-7.63 (m, 2H), 7.55 (d, J = 5.8 Hz, 1H),7.39-7.13 (m, 1H), 6.13 (s, 1H), 5.34 (d, J = 20.8 Hz, 1H), 4.84 (ddd, J= 8.3, 4.5, 2.5 Hz, 1H), 4.54 (dd, J = 9.4, 2.5 Hz, 1H), 4.39 (t, J =8.9 Hz, 1H), 3.86 (d, J = 36.7 Hz, 1H), 2.34 (d, J = 1.9 Hz, 3H), 1.77(d, J = 7.1 Hz, 3H), 1.01 (d, J = 6.8 Hz, 4H). HRMS(B) m/z 429.1783 (M +H)⁺. RT = 2.24 min. 122 and 123: Chiral separation was achieved bychiral SFC column (R)-3-(5-Fluoro-2-{1-[3-(3-fluoro- chromatography OJ-H21 × 250 mm, 15% MeOH in CO₂, 4-methyl-phenyl)- 80 g/min, UV233 nm togive (R)-3-(5-Fluoro-2-{(R)-1-[3-(3- [1,2,4]oxadiazol-5-yl]-fluoro-4-methyl-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-ethylamino}-pyrimidin-4-yl)-4-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one and((R)-1-hydroxy-ethyl)-oxazolidin-(R)-3-{2-[(S)-1-(5-Benzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]- 2-one5-fluoro-pyrimidin-4-yl}-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one. 122:First eluted product (58.7 mg). HRMS(B) m/z447.1573 (M + H)⁺. RT = 2.22min. 123: Second eluted product (36.4 mg). ¹H NMR (400 MHz, CDCl₃) δ8.17 (d, J = 2.7 Hz, 1H), 7.63 (dddd, J = 17.6, 9.8, 8.0, 1.7 Hz, 2H),7.32-7.14 (m, 1H), 5.96-5.72 (m, 1H), 5.22 (q, J = 6.9, 5.9 Hz, 1H),4.69-4.57 (m, 1H), 4.45 (t, J = 9.0 Hz, 1H), 4.35 (dd, J = 9.2, 5.6 Hz,1H), 4.14-3.96 (m, 1H), 2.25 (d, J = 1.9 Hz, 3H), 1.67 (dd, J = 11.7,7.0 Hz, 3H), 0.95 (t, J = 7.8 Hz, 3H). HRMS(B) m/z 447.1573 (M + H)⁺. RT= 2.22 min. 124 and 125: Chiral separation was achieved by chiral SFCcolumn (R)-3-(2-{1-[3-(3,4-Difluoro- chromatography AD-H 21 × 250 mm,25% IPA in CO₂, phenyl)-[1,2,4]oxadiazol-5-yl]- 75 g/min, UV226 nm togive (R)-3-(2-{(R)-1-[3-(3,4-Difluoro- ethylamino}-pyrimidin-4-yl)-4-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin- ((R)-1-hydroxy-ethyl)-oxazolidin-2-oneand (R)-3-(2-{(S)-1- 2-one[3-(3,4-Difluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one. 124: Firsteluted product (43.2 mg). HRMS(B) m/z 443.1112 (M + H)⁺. RT = 2.09 min.125: Second eluted product (40.7 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d,J = 5.8 Hz, 1H), 7.93-7.67 (m, 2H), 7.47 (d, J = 5.7 Hz, 1H), 7.30-7.10(m, 1H), 6.07 (s, 1H), 5.30 (s, 1H), 4.76 (ddd, J = 8.3, 4.6, 2.5 Hz,1H), 4.45 (dd, J = 9.4, 2.5 Hz, 1H), 4.31 (dd, J = 9.4, 8.4 Hz, 1H),4.02-3.52 (m, 1H), 1.69 (d, J = 7.1 Hz, 3H), 1.07-0.88 (m, 3H). HRMS(B)m/z 433.1109, (M + H)⁺. RT = 2.18 min. 126 and 127: Chiral separationwas achieved by chiral SFC column (R)-3-(2-{1-[3-(3,4-Dichloro-chromatography IA. 21 × 250 mm, 30% (70% phenyl)-isoxazol-5-yl]-MeOH:30% DCM) in CO₂, 70 g/min, UV239 nm to give (R)-3-ethylamino}-pyrimidin-4-yl)-4-(2-{(R)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-((R)-1-hydroxy-ethyl)-oxazolidin-ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)- 2-oneoxazolidin-2-one and (R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one. 126: First eluted product (37.4 mg).HRMS(B) m/z 464.0869 (M + H)⁺. RT = 2.63 min. 127: Second eluted product(27.3 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.76 (d, J = 2.0 Hz,1H), 7.53 (dd, J = 8.3, 2.0 Hz, 1H), 7.45 (d, J = 8.3 Hz, 2H), 6.37 (s,1H), 5.70 (s, 1H), 5.11 (s, 1H), 4.77 (ddd, J = 7.4, 4.6, 2.6 Hz, 1H),4.46 (dd, J = 9.4, 2.5 Hz, 1H), 4.31 (dd, J = 9.4, 8.4 Hz, 1H), 1.61 (d,J = 7.0 Hz, 3H), 0.86 (d, J = 7.5 Hz, 3H). HRMS(B) m/z 464.0855, (M +H)⁺. RT = 2.56 min. 128 and 129: Chiral separation was achieved bychiral SFC column (R)-3-(2-{1-[3-(2,4-Dichloro- chromatography OJ-H. 21× 250 mm, 15% MeOH in CO₂, phenyl)-isoxazol-5-yl]- 75 g/min, UV231 nm togive (R)-3-(2-{(R)-1-[3-(2,4-Dichloro- ethylamino}-pyrimidin-4-yl)-4-phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-((R)-1-hydroxy-ethyl)-oxazolidin- hydroxy-ethyl)-oxazolidin-2-one and(R)-3-(2-{(S)-1-[3-(2,4- 2-oneDichloro-phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one. 128: First eluted product(72.9 mg). HRMS(B) m/z 464.0869 (M + H)⁺. RT = 2.54 min. 129: Secondeluted product (36.5 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.39-8.11 (m, 1H),7.65 (d, J = 8.4 Hz, 1H), 7.56- 7.47 (m, 2H), 7.42-7.28 (m, 1H), 6.60(s, 1H), 5.80 (s, 1H), 5.27 (d, J = 37.0 Hz, 1H), 4.72-4.45 (m, 3H),4.31 (t, J = 8.7 Hz, 1H), 1.71 (d, J = 6.9 Hz, 3H), 1.19 (d, J = 6.4 Hz,3H). HRMS(B) m/z 464.0876, (M + H)⁺. RT = 2.55 min. 130 and 131: Chiralseparation was achieved by chiral SFC column(R)-3-(2-{1-[3-(3,4-Difluoro- chromatography ID 21 × 250 mm, 30% iIPA inCO₂, phenyl)-[1,2,4]oxadiazol-5-yl]- 75 g/min, UV233 nm to give and(R)-3-(2-{(S)-1-[3-(3,4- ethylamino}-5-fluoro-pyrimidin-4-Difluorophenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-5-fluoro-y|)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-onepyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one. 130: Firsteluted product (63.9 mg). HRMS(B) m/z 451.1324 (M + H)⁺. RT = 2.20 min.131: Second eluted product (58.1 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d,J = 2.8 Hz, 1H), 7.97-7.72 (m, 2H), 7.27 (dt, J = 9.9, 8.4 Hz, 1H), 6.09(s, 1H), 5.47-5.16 (m, 1H), 4.84-4.64 (m, 1H), 4.54 (t, J = 9.0 Hz, 1H),4.43 (dd, J = 9.1, 5.4 Hz, 1H), 3.87 (s, 1H), 1.76 (d, J = 7.1 Hz, 3H),1.04 (d, J = 6.5 Hz, 3H). HRMS(B) m/z 451.1324 (M + H)⁺. RT = 2.20 min.132 and 133: Chiral separation was achieved by chiral SFC column(R)-3-(2-{1-[3-(3,4-Dichloro- chromatography IC. 21 × 250 mm, 40% MeOHin CO₂, phenyl)-isoxazol-5-yl]- 80 g/min, UV239 nm to give(R)-3-(2-{(R)-1-[3-(3,4-Dichloro- ethylamino}-5-fluoro-pyrimidin-4-phenyl)-isoxazol-5-yl]-ethylamino}-5-fluoro-pyrimidin-4-yl)-y|)-4-((R)-1-hydroxy-ethyl)- 4-((R)-1-hydroxy-ethyl)-oxazolidin-2-oneand (R)-3-(2-{(S)- oxazolidin-2-one1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-5-fluoro-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one. 132:First eluted product (107 mg). HRMS(B) m/z 482.0781 (M + H)⁺. RT = 2.63min. 133: Second eluted product (61.1 mg). ¹H NMR (400 MHz, CDCl₃) δ8.22 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 1.9 Hz, 1H), 7.61 (dd, J = 8.3,2.0 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 6.45 (s, 1H), 5.72 (d, J = 7.6Hz, 1H), 5.25 (t, J = 7.1 Hz, 1H), 4.66-4.42 (m, 2H), 4.26 (t, J = 6.2Hz, 1H), 1.68 (d, J = 6.9 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H). HRMS(B) m/z482.0777 (M + H)⁺. RT = 2.63 min. 134 and 135: Chiral separation wasachieved by chiral SFC column (R)-3-(2-{1-[3-(2,4-Dichloro-chromatography AD-H, 21 × 250 mm, 35% IPA in CO₂,phenyl)-isoxazol-5-yl]- 75 g/min, UV237 nm to give(R)-3-(2-{(R)-1-[3-(2,4-Dichloro- ethylamino}-5-fluoro-pyrimidin-4-phenyl)-isoxazol-5-yl]-ethylamino}-5-fluoro-pyrimidin-4-yl)-y|)-4-((R)-1-hydroxy-ethyl)- 4-((R)-1-hydroxy-ethyl)-oxazolidin-2-oneand (R)-3-(2-{(S)- oxazolidin-2-one1-[3-(2,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-5-fluoro-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one. 134:First eluted product (53.4 mg). HRMS(B) m/z 482.0778 (M + H)⁺. RT = 2.54min. 135: Second eluted product (107 mg) ¹H NMR (400 MHz, CDCl₃) δ 8.21(d, J = 2.8 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H),7.42-7.22 (m, 1H), 6.60 (s, 1H), 5.88 (s, 1H), 5.24 (t, J = 6.7 Hz, 1H),4.98-4.71 (m, 1H), 4.63-4.40 (m, 2H), 3.83 (s, 1H), 1.70 (d, J = 7.1 Hz,3H), 1.05 (d, J = 6.4 Hz, 3H). HRMS(B) m/z 482.0774 (M + H)⁺. RT = 2.53min. 136 and 137: Chiral separation was achieved by chiral SFC column(R)-3-(2-{1-[4-(3-Chloro-4-fluoro- chromatography OD-H, 21 × 250 mm, 30%IPA in CO₂, phenyl)-thiazol-2-yl]-ethylamino}- 75 g/min, UV220 nm togive (R)-3-(2-{(R)-1-[4-(3-Chloro-4- pyrimidin-4-yl)-4-((R)-1-hydroxy-fluoro-phenyl)-thiazol-2-yl]-ethylamino}-pyrimidin-4-yl)-4-ethyl)-oxazolidin-2-one ((R)-1-hydroxy-ethyl)-oxazolidin-2-one and(R)-3-(2-{(S)-1-[4-(3-Chloro-4-fluoro-phenyl)-thiazol-2-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one. 136: Firsteluted product (76.9 mg). HRMS(B) m/z 464.0930 (M + H)⁺. RT = 2.50 min.137: Second eluted product (88.6 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d,J = 6.0 Hz, 1H), 7.95 (dd, J = 7.0, 2.2 Hz, 1H), 7.72 (ddd, J = 8.6,4.5, 2.2 Hz, 1H), 7.50 (d, J = 5.7 Hz, 1H), 7.34 (s, 1H), 7.18 (t, J =8.6 Hz, 1H), 5.61-5.35 (m, 1H), 4.75 (ddd, J = 8.1, 4.4, 2.4 Hz, 1H),4.45 (dd, J = 9.3, 2.7 Hz, 1H), 4.34 (t, J = 8.9 Hz, 1H), 3.87 (s, 1H),1.73 (d, J = 6.9 Hz, 3H), 0.90 (q, J = 6.9, 6.3 Hz, 3H). HRMS(B) m/z464.0940 (M + H)⁺. RT = 2.49 min. 138 and 139: Chiral separation wasachieved by chiral SFC column (R)-3-(5-fluoro-2-((1-(5-(3-chromatography (Column AD-H 20 × 250 mm 45% IPA 10 mM(trifluoromethyl)phenyl)pyrimidin- NH4OH in CO₂, flow 75 g/min, 238 nmUV collection) to 2-yl)ethyl)amino)pyrimidin-4-yl)- give(R)-3-(5-fluoro-2-(((S)-1-(5-(3- 4-((R)-1-hydroxyethyl)oxazolidin-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin- 2-one4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(5-fluoro-2-(((R)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one.138: First eluted product (6 mg) ¹H NMR (400 MHz, CDCl₃) δ 8.84 (s, 2H),8.15 (d, J = 2.8 Hz, 1H), 7.76-7.55 (m, 3H), 6.17 (br s, 1H), 5.24 (t, J= 7.1 Hz, 1H), 4.56 (d, J = 7.4 Hz, 1H), 4.47 (t, J = 8.8 Hz, 1H), 4.33(dd, J = 9.0, 5.1 Hz, 1H), 4.00 (br s, 1H), 1.59 (d, J = 6.9 Hz, 3H),1.06 (br d, J = 5.7 Hz, 3H). HRMS(B) m/z 493.1587 (M + H)⁺. 139: Secondeluted product (10 mg) ¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 2H), 8.14 (d,J = 2.9 Hz, 1H), 7.77-7.55 (m, 4H), 6.32 (br s, 1H), 5.18 (br s, 1H),4.49-4.29 (m, 3H), 3.96 (p, J = 6.1 Hz, 1H), 2.69 (br s, 1H), 1.58 (d, J= 7.0 Hz, 3H), 1.15 (d, J = 5.9 Hz, 3H). HRMS(B) m/z 493.1591 (M + H)⁺.140 and 141: Chiral separation was achieved by chiral SFC column(4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column OD 20 × 250 mm25% MeOH in ((1-(2-phenylthiazol-5- CO₂, flow 75 g/min, 238 nm UVcollection) to give(R)-4- yl)ethyl)amino)pyrimidin-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(2-phenylthiazol-5-yl)oxazolidin-2-one yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and(R)-4- ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(2-phenylthiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(2-phenylthiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 140: First eluted product(48 mg) ¹H NMR (400 MHz, CDCl₃) δ 10.83 (s, 1H), 8.13-7.69 (m, 5H), 7.47(d, J = 4.6 Hz, 4H), 5.31-5.14 (m, 1H), 4.82 (d, J = 7.7 Hz, 1H), 4.66(dd, J = 9.6, 2.2 Hz, 1H), 4.46 (dd, J = 9.6, 8.0 Hz, 1H), 3.38 (d, J =9.6 Hz, 1H), 1.84 (d, J = 6.8 Hz, 3H), 1.55- 1.09 (m, 1H), 1.03-0.71 (m,4H). HRMS(B) m/z 411.1365. Chiral RT = 2.90 min 141: Second elutedproduct (46 mg) ¹H NMR (400 MHz, CDCl₃) δ 11.03 (s, 1H), 8.11-7.64 (m,5H), 7.49 (d, J = 4.9 Hz, 3H), 5.52-5.10 (m, 1H), 4.70 (dd, J = 23.0,8.0 Hz, 2H), 4.42 (t, J = 8.6 Hz, 2H), 1.86 (d, J = 6.8 Hz, 3H), 1.53-1.08 (m, 4H), 0.99-0.61 (m, 1H). HRMS(B) m/z 411.1365. Chiral RT = 4.00min 142 and 143: Chiral separation was achieved by chiral SFC column(4R)-3-(2-((1-(3-(3- chromatography (Column AD 20 × 250 mm 20% MeOH inchlorophenyl)-1,2,4-oxadiazol-5- CO₂, flow 90 g/min, 238 nm UVcollection) to give (R)-3-(2- yl)ethyl)amino)pyrimidin-4-yl)-4-(((R)-1-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 142: First eluted product(15.5 mg): ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J = 5.8 Hz, 4H), 7.79 (dd,J = 7.6, 1.8 Hz, 4H), 7.56-7.26 (m, 15H), 5.83 (s, 4H), 5.17 (s, 4H),4.57 (q, J = 6.1 Hz, 4H), 4.39 (dd, J = 9.3, 2.5 Hz, 4H), 4.29- 4.04 (m,9H), 3.96 (p, J = 6.2 Hz, 1H), 2.96 (s, 4H), 1.88- 1.56 (m, 5H),1.49-1.01 (m, 28H), 0.93-0.59 (m, 4H). HRMS(B) m/z 430.1156. Chiral RT =3.40 min 143: Second eluted product (10 mg) ¹H NMR (400 MHz, CDCl₃) δ8.25 (d, J = 5.8 Hz, 3H), 7.91 (dd, J = 7.7, 1.8 Hz, 3H), 7.62-7.52 (m,6H), 7.43 (dtd, J = 25.2, 7.5, 1.6 Hz, 6H), 6.30 (s, 3H), 5.40 (s, 3H),4.87 (ddd, J = 8.3, 4.3, 2.3 Hz, 3H), 4.55 (dd, J = 9.5, 2.5 Hz, 3H),4.39 (t, J = 8.9 Hz, 3H), 4.10-3.75 (m, 4H), 3.50 (s, 3H), 3.18-2.93 (m,3H), 1.72 (d, J = 6.8 Hz, 0H), 1.39-1.16 (m, 5H), 1.10-0.93 (m, 9H),0.93-0.76 (m, 2H). HRMS(B) m/z 430.1156. Chiral RT = 4.80 min 144 and145: Chiral separation was achieved by chiral SFC column(4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column ID 21 × 250 mm25% MeOH in ((1-(3-(4-isopropylphenyl)-1,2,4- CO₂, flow 75 g/min, 238 nmUV collection) to give (R)-4- oxadiazol-5-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(4-isopropylphenyl)-yl)ethyl)amino)pyrimidin-4-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-yl)oxazolidin-2-one 2-one and(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 144: First eluted product(36 mg): (CDCl₃) δ 8.24 (d, J = 5.7 Hz, 1H), 8.06-7.88 (m, 2H), 7.50 (d,J = 5.8 Hz, 1H), 7.41-7.32 (m, 2H), 6.05 (s, 1H), 5.22 (s, 1H), 4.71 (s,1H), 4.49 (dd, J = 9.3, 2.5 Hz, 1H), 4.43-4.14 (m, 2H), 4.12- 3.99 (m,0H), 3.51 (s, 1H), 3.37 (s, 1H), 2.98 (hept, J = 6.9 Hz, 1H), 2.04-1.73(m, 1H), 1.44-1.17 (m, 11H). HRMS(B) m/z 438.2016. Chiral RT = 3.20 min145: Second eluted product (36 mg): CDCl₃) δ 8.25 (d, J = 5.7 Hz, 1H),8.05-7.91 (m, 2H), 7.54 (d, J = 5.7 Hz, 1H), 7.42-7.31 (m, 2H), 6.23 (s,1H), 5.33 (d, J = 10.8 Hz, 1H), 4.85 (ddd, J = 8.5, 4.5, 2.3 Hz, 1H),4.56 (dd, J = 9.4, 2.5 Hz, 1H), 1.84-1.73 (m, 3H), 4.39 (t, J = 8.9 Hz,1H), 3.86 (s, 1H), 3.51 (s, 1H), 3.15 (s, 1H), 2.97 (hept, J = 7.0 Hz,1H), 1.94 (d, J = 7.1 Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H), 0.99 (d, J =6.9 Hz, 3H). HRMS(B) m/z 438.2016. Chiral RT = 4.60 min 146 and 147:Chiral separation was achieved by chiral SFC column(4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column AD-H 21 × 250mm 25% MeOH in ((1-(3-(2- CO₂, flow 75 g/min, 238 nm UV collection) togive (R)-4- (trifluoromethoxy)phenyl)-1,2,4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(2- oxadiazol-5-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5- yl)ethyl)amino)pyrimidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-yl)oxazolidin-2-one ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(2-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 146: First eluted product(8.3 mg): (CDCl₃) δ 8.25 (d, J = 5.9 Hz, 1H), 8.07 (dd, J = 7.8, 1.8 Hz,1H), 7.69-7.39 (m, 4H), 5.73 (s, 1H), 5.26 (s, 1H), 4.78-4.57 (m, 1H),4.48 (dd, J = 9.3, 2.3 Hz, 1H), 4.39-4.00 (m, 2H), 3.52 (s, 1H), 2.93(s, 1H), 1.80 (d, J = 7.1 Hz, 3H), 1.62 (s, 3H), 1.21 (dd, J = 18.6, 6.3Hz, 5H). HRMS(B) m/z 480.1369. Chiral RT = 2.10 min 147: Second elutedproduct (38.5 mg): (CDCl₃) δ 8.25 (d, J = 5.8 Hz, 1H), 8.10 (dd, J =8.0, 1.7 Hz, 1H), 7.67-7.52 (m, 2H), 7.51-7.40 (m, 2H), 5.88 (s, 1H),5.39 (s, 1H), 4.86 (ddd, J = 8.5, 4.6, 2.5 Hz, 1H), 1.75-1.64 (m, 1H),4.55 (dd, J = 9.4, 2.5 Hz, 1H), 4.39 (t, J = 8.9 Hz, 1H), 4.14- 3.58 (m,1H), 2.86 (s, 1H), 1.80 (d, J = 7.1 Hz, 3H), 1.23 (d, J = 6.1 Hz, 1H),1.00 (s, 3H). HRMS(B) m/z 480.1369. Chiral RT = 2.55 min 148 and 149:Chiral separation was achieved by chiral SFC column(4R)-3-(2-((1-(3-(4-fluoro-3- chromatography (Column AD-H 21 × 250 mm15% MeOH in methylphenyl)-1,2,4-oxadiazol-5- CO₂, flow 80 g/min, 238 nmUV collection) to give(R)-3-(2- yl)ethyl)amino)pyrimidin-4-yl)-4-(((R)-1-(3-(4-fluoro-3-methylphenyl)-1,2,4-oxadiazol-5-((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-fluoro-3-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one148: First eluted product (13 mg): (CDCl₃) δ 8.25 (d, J = 5.8 Hz, 1H),8.03-7.80 (m, 2H), 7.52 (d, J = 5.7 Hz, 1H), 7.13 (t, J = 8.9 Hz, 1H),5.85 (s, 1H), 5.23 (s, 1H), 4.69 (d, J = 8.4 Hz, 1H), 4.50 (dd, J = 9.5,2.5 Hz, 1H), 4.41-4.04 (m, 2H), 3.51 (s, 2H), 3.11 (s, 1H), 2.36 (d, J =2.0 Hz, 3H), 1.78 (d, J = 7.1 Hz, 3H), 1.21 (d, J = 6.4 Hz, 4H). HRMS(B)m/z 428.1608 Chiral RT = 4.25 min 149: Second eluted product (49 mg):(CDCl₃) δ 8.25 (d, J = 5.7 Hz, 1H), 8.01-7.80 (m, 2H), 7.56 (d, J = 5.7Hz, 1H), 7.12 (t, J = 8.9 Hz, 1H), 5.76 (s, 1H), 5.46-5.12 (m, 1H), 4.85(ddd, J = 8.4, 4.6, 2.4 Hz, 1H), 4.55 (dd, J = 9.5, 2.5 Hz, 1H), 4.40(t, J = 8.9 Hz, 1H), 2.89 (s, 1H), 2.35 (d, J = 2.0 Hz, 3H), 1.79 (d, J= 7.1 Hz, 3H), 1.43-1.13 (m, 2H), 1.16-0.74 (m, 3H). HRMS(B) m/z428.1608 Chiral RT = 6.15 min 150 and 151: Chiral separation wasachieved by chiral SFC column (4R)-3-(2-((1-(3-(4-ethylphenyl)-chromatography (Column ID 21 × 250 mm 40% MeOH + 1,2,4-oxadiazol-5- 10mM NH4OH in CO₂, flow 75 g/min, 238 nm UV yl)ethyl)amino)-5- collection)to give (R)-3-(2-(((R)-1-(3-(4-ethylphenyl)-1,2,4-fluoropyrimidin-4-yl)-4-((R)-1-oxadiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one hydroxyethyl)oxazolidin-2-one and(R)-3-(2-(((S)-1-(3-(4-ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 150: Firsteluted product (106 mg): (CDCl₃) δ 8.24 (d, J = 2.9 Hz, 1H), 7.99-7.87(m, 2H), 7.38-7.22 (m, 2H), 5.96 (d, J = 7.1 Hz, 1H), 5.31 (d, J = 9.1Hz, 1H), 4.56-4.25 (m, 4H), 3.49 (s, 4H), 3.30 (d, J = 13.4 Hz, 1H),2.72 (q, J = 7.6 Hz, 2H), 1.68 (s, 0H), 1.66-1.38 (m, 2H), 1.35-1.08 (m,7H). HRMS(B) m/z 442.1765 Chiral RT = 2.80 min 151: Second elutedproduct (10.6 mg): (CDCl₃) δ 8.27 (d, J = 2.7 Hz, 2H), 8.05-7.87 (m,4H), 7.39-7.23 (m, 4H), 5.77 (d, J = 6.7 Hz, 2H), 5.30-5.17 (m, 2H),4.73 (dt, J = 10.7, 5.1 Hz, 2H), 4.54 (t, J = 9.1 Hz, 2H), 1.85-1.73 (m,6H), 4.44 (dd, J = 9.2, 5.6 Hz, 2H), 3.86-3.59 (m, 2H), 3.51 (s, 2H),2.72 (q, J = 7.6 Hz, 6H), 1.37-1.19 (m, 8H), 1.01 (d, J = 6.9 Hz, 8H),0.92-0.69 (m, 1H). HRMS(B) m/z 442.1765 Chiral RT = 4.05 min 152 and153: Chiral separation was achieved by chiral SFC column(4R)-3-(2-((1-(5-(3,4- chromatography (Column IC 4.6 × 100 mm 5-55%IPA + 20 dimethylphenyl)-1,3,4-oxadiazol- mM NH4OH/in CO₂, flow 75g/min, 238 nm UV collection) 2-yl)ethyl)amino)pyrimidin-4-yl)- togive(R)-3-(2-(((S)-1-(5-(3,4-dimethylphenyl)-1,3,4-4-((R)-1-hydroxyethyl)oxazolidin-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 2-onehydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-(5-(3,4-dimethylphenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 152: First eluted product(25 mg): (CDCl₃) δ 8.22 (d, J = 5.8 Hz, 1H), 7.84-7.79 (m, 1H), 7.75(dd, J = 8.0, 1.8 Hz, 1H), 7.48 (d, J = 5.7 Hz, 1H), 7.34-7.20 (m, 1H),5.90 (d, J = 4.6 Hz, 1H), 5.18 (s, 1H), 4.93-4.74 (m, 1H), 1.85-1.71 (m,3H), 4.61 (dd, J = 9.3, 2.2 Hz, 1H), 4.50-4.38 (m, 1H), 4.33 (t, J = 8.8Hz, 1H), 4.21 (s, 1H), 4.11-4.00 (m, 0H), 2.34 (s, 6H), 1.22 (dd, J =10.3, 6.3 Hz, 5H). HRMS(B) m/z 425.1982. Chiral RT = 1.75 min 153:Second eluted product (25 mg): (CDCl₃) δ 8.23 (d, J = 5.7 Hz, 1H), 7.81(d, J = 1.9 Hz, 1H), 7.75 (dd, J = 7.8, 1.9 Hz, 1H), 7.53 (d, J = 5.7Hz, 1H), 7.28 (d, J = 3.6 Hz, 1H), 5.67 (d, J = 6.0 Hz, 1H), 5.48-5.30(m, 1H), 5.02-4.91 (m, 1H), 4.62 (dd, J = 9.5, 2.3 Hz, 1H), 4.42 (dd, J= 9.4, 8.3 Hz, 1H), 3.88 (s, 2H), 2.34 (s, 6H), 1.79 (d, J = 7.2 Hz,3H), 1.63 (s, 1H), 1.33-1.16 (m, 1H), 1.06 (d, J = 6.4 Hz, 3H). HRMS(B)m/z 425.1981. Chiral RT = 2.15 min 154 and 155: Chiral separation wasachieved by chiral SFC column (4R)-4-((R)-1-hydroxyethyl)-3-(2-chromatography (Column OJ-H 21 × 250 mm 20% MeOH + 5((1-(3-(isoquinolin-8-yl)-1,2,4- mM NH4OH/CO₂/in CO₂, flow 75 g/min, 238nm UV oxadiazol-5- collection) to give(R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3- yl)ethyl)amino)pyrimidin-4-(isoquinolin-8-yl)-1,2,4-oxadiazol-5- yl)oxazolidin-2-oneyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(isoquinolin-8-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 154: Firsteluted product (10 mg): (CDCl₃) δ 8.47-8.11 (m, 4H), 7.99 (d, J = 8.1Hz, 2H), 7.83 (t, J = 7.9 Hz, 3H), 7.57 (s, 4H), 5.94 (s, 2H), 5.47 (s,2H), 4.95-4.65 (m, 2H), 4.42 (d, J = 88.6 Hz, 6H), 3.52 (s, 5H),2.09-1.51 (m, 1H), 1.47-0.99 (m, 7H), 0.96-0.68 (m, 1H). HRMS(B) m/z447.1655. Chiral RT = 2.55 min 155: Second eluted product (28.7 mg):(CDCl₃) δ 10.26 (s, 2H), 8.63 (s, 2H), 8.28 (d, J = 7.3 Hz, 4H), 7.97(d, J = 8.2 Hz, 2H), 7.77 (t, J = 7.8 Hz, 3H), 7.58 (d, J = 5.3 Hz, 2H),6.08 (s, 2H), 5.62 (p, J = 7.1 Hz, 2H), 5.11-4.84 (m, 2H), 4.61 (dd, J =8.8, 2.7 Hz, 2H), 4.41 (t, J = 8.9 Hz, 2H), 4.30 (s, 2H), 3.89 (s, 2H),3.63-3.43 (m, 8H), 1.73 (d, J = 33.4 Hz, 0H), 1.32 (q, J = 5.2 Hz, 3H),1.04 (d, J = 7.1 Hz, 6H). HRMS(B) m/z 447.1655. Chiral RT = 2.90 min 156and 157: Chiral separation was achieved by chiral SFC column(4R)-3-(2-((1-(3-(4-chloro-2- chromatography (Column IC 4.6 × 100 mm5-55% IPA + 20 (trifluoromethyl)phenyl)-1,2,4- mM NH4OH in CO₂, flow 75g/min, 238 nm UV collection) oxadiazol-5- togive(R)-3-(2-(((R)-1-(3-(4-chloro-2- yl)ethyl)amino)pyrimidin-4-yl)-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-chloro-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one156: First eluted product (50 mg): (CDCl₃) δ 8.16 (d, J = 5.9 Hz, 1H),7.81-7.64 (m, 1H), 7.57 (dd, J = 8.3, 2.1 Hz, 1H), 7.48 (d, J = 5.8 Hz,1H), 6.50 (s, 1H), 5.35 (s, 1H), 4.78 (ddd, J = 7.4, 4.6, 2.4 Hz, 1H),4.45 (dd, J = 9.3, 2.5 Hz, 1H), 4.31 (dd, J = 9.4, 8.3 Hz, 1H), 3.92 (d,J = 48.4 Hz, 1H), 3.41 (s, 1H), 3.18-2.11 (m, 1H), 1.70 (d, J = 7.1 Hz,3H), 1.30-1.08 (m, 1H), 0.93 (d, J = 7.6 Hz, 3H). HRMS(B) m/z 498.1030.Chiral RT = 2.03 min 157: Second eluted product (15 mg): (CDCl₃) δ 8.15(d, J = 6.2 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H),7.59 (dd, J = 8.4, 2.1 Hz, 1H), 7.47 (d, J = 5.6 Hz, 1H), 5.96 (s, 1H),5.17 (s, 1H), 4.73-4.47 (m, 1H), 4.40 (dd, J = 9.2, 2.4 Hz, 1H), 4.21(d, J = 37.9 Hz, 1H), 3.42 (s, 3H), 1.60 (s, 3H), 1.33-0.99 (m, 1H),0.92-0.64 (m, 1H). HRMS(B) m/z 498.1030. Chiral RT = 2.18 min 158 and159: Chiral separation was achieved by chiral SFC column(4R)-3-(5-fluoro-2-((1-(3-(4- chromatography (Column ID 21 × 250 mm 40%MeOH + isopropylphenyl)-1,2,4- 10 mM NH4OH in CO₂, flow 75 g/min, 238 nmUV oxadiazol-5- collection) to give (R)-3-(5-fluoro-2-(((R)-1-(3-(4-yl)ethyl)amino)pyrimidin-4-yl)-4- isopropylphenyl)-1,2,4-oxadiazol-5-((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(5-fluoro-2-(((S)-1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one158: First eluted product (51 mg): (CDCl₃) δ 8.17 (d, J = 2.7 Hz, 1H),7.92-7.83 (m, 2H), 7.30-7.21 (m, 2H), 5.83 (d, J = 6.5 Hz, 1H), 5.21(dd, J = 13.8, 6.9 Hz, 1H), 4.77- 4.57 (m, 1H), 4.46 (t, J = 9.1 Hz,1H), 4.36 (dd, J = 9.2, 5.6 Hz, 1H), 3.96 (p, J = 6.1 Hz, 1H), 3.63 (s,1H), 2.88 (hept, J = 7.0 Hz, 1H), 1.76-1.60 (m, 3H), 1.19 (d, J = 7.0Hz, 7H), 1.14 (d, J = 6.1 Hz, 4H), 0.93 (d, J = 7.0 Hz, 3H). HRMS(B) m/z456.1921 Chiral RT = 2.60 min 159: Second eluted product (54 mg):(CDCl₃) δ 8.24 (d, J = 3.0 Hz, 1H), 8.02-7.89 (m, 2H), 7.39-7.30 (m,2H), 5.98 (d, J = 7.2 Hz, 1H), 5.31 (d, J = 8.6 Hz, 1H), 4.52-4.27 (m,4H), 1.83-1.67 (m, 3H), 3.49 (s, 1H), 2.97 (hept, J = 6.9 Hz, 1H), 1.28(d, J = 6.9 Hz, 6H), 1.21 (dd, J = 11.1, 6.2 Hz, 5H). HRMS(B) m/z456.1921. Chiral RT = 3.70 min 160 and 161: Chiral separation wasachieved by chiral SFC column (4R)-4-((R)-1-hydroxyethyl)-3-(2-chromatography (Column AD-H 21 × 250 mm 25% IPA in((1-(3-(3-(trifluoromethyl)phenyl)- CO₂, flow 75 g/min, 238 nm UVcollection) to give(R)-4- 1,2,4-oxadiazol-5-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(3- yl)ethyl)amino)pyrimidin-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5- yl)oxazolidin-2-oneyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 160: First eluted product(15 mg): (CDCl₃) δ 8.27 (d, J = 2.0 Hz, 1H), 8.16 (t, J = 7.3 Hz, 2H),7.71 (d, J = 7.9 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 1.74-1.56 (m, 3H),7.50- 7.37 (m, 1H), 6.06 (s, 1H), 5.26 (d, J = 47.9 Hz, 1H), 4.59 (d, J= 9.5 Hz, 1H), 4.52-4.23 (m, 2H), 1.14 (dd, J = 6.3, 4.8 Hz, 5H),1.03-0.88 (m, 2H), 0.88-0.71 (m, 0H), 4.85- 4.72 (m, 0H), 4.16 (s, 1H),3.97 (p, J = 6.1 Hz, 0H), 2.88 (s, 1H), 2.34-1.77 (m, 1H). HRMS(B) m/z464.1420. Chiral RT = 2.10 min 161: Second eluted product (38.5 mg):(CDCl₃) δ 8.36 (d, J = 1.8 Hz, 1H), 8.31-8.19 (m, 2H), 7.87-7.76 (m,1H), 7.64 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 5.7 Hz, 1H), 6.04 (s, 1H),5.42 (s, 1H), 4.87 (ddd, J = 8.4, 4.7, 2.5 Hz, 1H), 4.55 (dd, J = 9.5,2.5 Hz, 1H), 4.41 (dd, J = 9.5, 8.3 Hz, 1H), 4.11-3.72 (m, 1H), 2.83 (s,1H), 2.13-1.57 (m, 1H), 1.23 (d, J = 6.1 Hz, 2H), 1.05 (d, J = 9.5 Hz,3H). HRMS(B) m/z 464.1420 Chiral RT = 2.55 min 162 and 163: Chiralseparation was achieved by chiral SFC column(4R)-3-(2-((1-(3-(4-fluoro-3- chromatography (Column AD-H 21 × 250 mm10% MeOH in (trifluoromethoxy)phenyl)-1,2,4- CO₂, flow 80 g/min, 238 nmUV collection) to give (R)-3-(2- oxadiazol-5-(((R)-1-(3-(4-fluoro-3-(trifluoromethoxy)phenyl)-1,2,4-yl)ethyl)amino)pyrimidin-4-yl)-4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-((R)-1-hydroxyethyl)oxazolidin- hydroxyethyl)oxazolidin-2-one and(R)-3-(2-(((S)-1-(3-(4- 2-onefluoro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one162: First eluted product (13 mg): CDCl₃) δ 8.24 (d, J = 5.9 Hz, 1H),8.04 (ddt, J = 13.4, 6.5, 1.9 Hz, 2H), 7.55 (d, J = 5.7 Hz, 1H), 7.35(t, J = 9.0 Hz, 1H), 6.08 (s, 1H), 5.27 (s, 1H), 4.78-4.58 (m, 1H), 4.52(dd, J = 9.3, 2.5 Hz, 1H), 4.44 (d, J = 15.7 Hz, 1H), 4.25 (d, J = 11.2Hz, 1H), 3.51 (s, 2H), 2.97 (s, 1H), 1.98-1.67 (m, 0H), 1.22 (d, J = 6.5Hz, 4H). HRMS(B) m/z 498.1275 Chiral RT = 3.60 min 163: Second elutedproduct (40 mg): (CDCl₃) δ 8.25 (d, J = 6.2 Hz, 1H), 8.13-7.98 (m, 2H),7.57 (d, J = 5.6 Hz, 1H), 7.35 (dd, J = 9.4, 8.6 Hz, 1H), 5.77 (s, 1H),5.40 (s, 1H), 4.85 (ddd, J = 8.2, 4.7, 2.5 Hz, 1H), 4.54 (dd, J = 9.4,2.5 Hz, 1H), 4.41 (dd, J = 9.4, 8.3 Hz, 1H), 3.87 (t, J = 65.5 Hz, 1H),3.52 (s, 1H), 2.76 (s, 1H), 1.79 (d, J = 7.1 Hz, 3H), 1.34-1.25 (m, 1H),1.05 (s, 3H). ). HRMS(B) m/z 498.1275 Chiral RT = 4.80 min 164 and 165:Chiral separation was achieved by chiral SFC column (4R)-3-(2-((1-(3-(3-chromatography (Column AD-H 21 × 250 mm 35% IPA in(difluoromethoxy)phenyl)-1,2,4- CO₂, flow 75 g/min, 238 nm UVcollection) to give (R)-3-(2- oxadiazol-5-(((R)-1-(3-(3-(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- ((R)-1-hydroxyethyl)oxazolidin-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(3- 2-one(difluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one164: First eluted product (18 mg): (CDCl₃) δ 8.25 (d, J = 5.8 Hz, 1H),7.92 (dt, J = 7.7, 1.4 Hz, 1H), 7.83 (t, J = 2.0 Hz, 1H), 7.62-7.43 (m,2H), 7.36-7.24 (m, 1H), 6.61 (t, J = 73.3 Hz, 1H), 6.25 (d, J = 59.0 Hz,1H), 5.36 (d, J = 30.2 Hz, 1H), 4.86 (ddd, J = 8.5, 4.8, 2.5 Hz, 1H),4.55 (dd, J = 9.3, 2.5 Hz, 1H), 4.40 (t, J = 8.9 Hz, 1H), 3.51 (s, 2H),1.83 (s, 1H), 1.34-1.16 (m, 1H), 1.02 (s, 3H). HRMS(B) m/z 462.1463Chiral RT = 1.65 min 165: Second eluted product (63 mg): (CDCl₃) δ 8.25(d, J = 5.8 Hz, 1H), 7.92 (dt, J = 7.7, 1.4 Hz, 1H), 7.83 (t, J = 2.0Hz, 1H), 7.62-7.43 (m, 2H), 7.36-7.24 (m, 1H), 6.61 (t, J = 73.3 Hz,1H), 6.25 (d, J = 59.0 Hz, 1H), 5.36 (d, J = 30.2 Hz, 1H), 4.86 (ddd, J= 8.5, 4.8, 2.5 Hz, 1H), 4.55 (dd, J = 9.3, 2.5 Hz, 1H), 4.40 (t, J =8.9 Hz, 1H), 3.51 (s, 2H), 1.83 (s, 1H), 1.34-1.16 (m, 1H), 1.02 (s,3H). HRMS(B) m/z 462.1463 Chiral RT = 2.10 min 166 and 167: Chiralseparation was achieved by chiral SFC column(4R)-3-(2-((1-(3-(4-chloro-3- chromatography (Column AD-H 21 × 250 mm30% MeOH in methoxyphenyl)-1,2,4-oxadiazol- CO₂, flow 80 g/min, 238 nmUV collection) to give (R)-3-(2- 5-yl)ethyl)amino)pyrimidin-4-yl)-(((R)-1-(3-(4-chloro-3-methoxyphenyl)-1,2,4-oxadiazol-5-4-((R)-1-hydroxyethyl)oxazolidin-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 2-onehydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-chloro-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one166: First eluted product (10 mg): (CDCl₃) δ 8.38-8.18 (m, 1H), 7.61(hept, J = 2.3, 1.9 Hz, 2H), 7.57-7.45 (m, 2H), 5.89 (s, 1H), 5.33 (s,2H), 4.70 (s, 1H), 4.50 (dd, J = 9.4, 2.4 Hz, 1H), 4.00 (s, 2H), 3.07(s, 1H), 1.75 (s, 2H), 1.34-1.11 (m, 6H). HRMS(B) m/z 461.1464. RT =2.24 min. Chiral RT = 2.85 min 167: Second eluted product (120 mg):(CDCl₃) δ 8.25 (d, J = 5.8 Hz, 1H), 7.63 (d, J = 7.5 Hz, 2H), 7.57 (d, J= 5.7 Hz, 1H), 7.52-7.46 (m, 1H), 5.74 (s, 1H), 5.35 (d, J = 20.7 Hz,1H), 4.85 (ddd, J = 8.3, 4.7, 2.4 Hz, 1H), 4.54 (dd, J = 9.5, 2.5 Hz,1H), 4.40 (dd, J = 9.4, 8.3 Hz, 1H), 4.01 (s, 3H), 3.52 (s, 3H), 2.85(s, 1H), 1.88-1.76 (m, 2H), 1.67 (s, 1H), 1.23 (d, J = 6.1 Hz, 1H), 1.03(s, 3H). HRMS(B) m/z 461.1464. RT = 2.23 min. Chiral RT = 3.55 min 168and 169: Chiral separation was achieved by chiral SFC column(4R)-3-(2-((1-(3-(2,2- chromatography (Column AD-H 21 × 250 mm 35% IPAin difluorobenzo[d][1,3]dioxol-5-yl)- CO₂, flow 75 g/min, 238 nm UVcollection) to give (R)-3-(2- 1,2,4-oxadiazol-5-(((R)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1,2,4-yl)ethyl)amino)pyrimidin-4-yl)-4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-((R)-1-hydroxyethyl)oxazolidin- hydroxyethyl)oxazolidin-2-one and(R)-3-(2-(((S)-1-(3-(2,2- 2-onedifluorobenzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one168: First eluted product (14 mg): (CDCl₃) δ 8.23 (d, J = 6.2 Hz, 1H),7.86 (dd, J = 8.2, 1.8 Hz, 1H), 7.78 (d, J = 1.7 Hz, 1H), 7.55 (d, J =5.7 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 6.46 (s, 1H), 5.29 (d, J = 27.6Hz, 1H), 4.90-4.58 (m, 1H), 4.52 (dd, J = 9.4, 2.5 Hz, 1H), 4.46-4.17(m, 2H), 3.51 (s, 1H), 2.93 (s, 2H), 1.22 (dd, J = 8.8, 6.2 Hz, 4H).HRMS(B) m/z 476.1256. RT = 2.42 min. Chiral RT = 1.65 min 169: Secondeluted product (62 mg): (CDCl₃) δ 8.15 (d, J = 5.8 Hz, 1H), 7.79 (dd, J= 8.3, 1.7 Hz, 1H), 7.69 (d, J = 1.7 Hz, 1H), 7.47 (d, J = 5.8 Hz, 1H),7.09 (d, J = 8.4 Hz, 1H), 6.38 (s, 1H), 5.26 (d, J = 24.5 Hz, 1H), 4.76(ddd, J = 8.5, 4.6, 2.4 Hz, 1H), 4.46 (dd, J = 9.3, 2.5 Hz, 1H), 4.32(t, J = 8.9 Hz, 1H), 4.06-3.60 (m, 1H), 3.42 (s, 2H), 1.86 (d, J = 7.1Hz, 3H), 1.14 (d, J = 6.1 Hz, 1H), 1.04-0.72 (m, 3H). HRMS(B) m/z476.1256. RT = 2.43 min. Chiral RT = 1.95 min 170 and 171: Chiralseparation was achieved by chiral SFC column(4R)-3-(2-((1-(3-(4-chloro-3- chromatography (Column AD-H 21 × 250 mm20% MeOH in (trifluoromethyl)phenyl)-1,2,4- CO₂, flow 80 g/min, 238 nmUV collection) to give (R)-3-(2- oxadiazol-5-(((R)-1-(3-(4-chloro-3-(trifluoromethyl)phenyl)-1,2,4-yl)ethyl)amino)pyrimidin-4-yl)-4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-((R)-1-hydroxyethyl)oxazolidin- hydroxyethyl)oxazolidin-2-one and(R)-3-(2-(((S)-1-(3-(4- 2-onechloro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one170: First eluted product (23 mg): (CDCl₃) δ 8.42 (d, J = 2.0 Hz, 1H),8.25 (d, J = 5.9 Hz, 1H), 8.18 (dd, J = 8.4, 2.1 Hz, 1H), 7.66 (d, J =8.4 Hz, 1H), 7.55 (d, J = 5.7 Hz, 1H), 5.81 (s, 1H), 5.33 (s, 2H), 4.66(s, 1H), 4.52 (dd, J = 9.3, 2.5 Hz, 1H), 4.46-4.14 (m, 2H), 2.84 (s,1H), 1.79 (d, J = 7.0 Hz, 3H), 1.23 (d, J = 6.5 Hz, 4H). HRMS(B) m/z498.1030. RT = 2.57 min. Chiral RT = 2.70 min 171: Second eluted product(83 mg): (CDCl₃) δ 8.42 (d, J = 2.0 Hz, 1H), 8.31-8.12 (m, 2H), 7.62(dd, J = 26.0, 7.1 Hz, 2H), 1.92-1.70 (m, 3H), 6.31 (s, 1H), 5.32 (s,2H), 4.86 (ddd, J = 8.3, 4.8, 2.4 Hz, 1H), 4.54 (dd, J = 9.3, 2.5 Hz,1H), 4.42 (dd, J = 9.4, 8.3 Hz, 1H), 4.13-3.77 (m, 1H), 2.71 (s, 2H),1.44-0.84 (m, 4H). HRMS(B) m/z 498.1030. RT = 2.57 min. Chiral RT = 3.60min 172 and 173: Chiral separation was achieved by chiral SFC column(4R)-3-(2-((1-(3-(4-ethylphenyl)- chromatography (Column IA 21 × 250 mm40% IPA + 10 mM 1,2,4-oxadiazol-5- NH4OH in CO₂, flow 75 g/min, 238 nmUV collection) to yl)ethyl)amino)pyrimidin-4-yl)-4- give(R)-3-(2-(((R)-1-(3-(4-ethylphenyl)-1,2,4-oxadiazol-5-((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-ethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 172: First eluted product (73mg): (CDCl₃) δ 8.24 (d, J = 5.8 Hz, 1H), 8.05-7.87 (m, 2H), 7.50 (d, J =5.8 Hz, 1H), 7.41-7.30 (m, 2H), 5.98 (s, 1H), 1.57-1.47 (m, 0H), 5.22(s, 1H), 4.71 (s, 1H), 4.13-4.00 (m, 0H), 4.48 (dd, J = 9.5, 2.4 Hz,1H), 4.33 (s, 1H), 4.18 (s, 1H), 3.51 (d, J = 5.3 Hz, 0H), 3.30 (s, 1H),2.73 (q, J = 7.6 Hz, 2H), 1.78 (d, J = 7.1 Hz, 3H), 1.39-1.08 (m, 7H).HRMS(B) m/z 424.1859. RT = 2.39 min. Chiral RT = 2.15 min 173: Secondeluted product (17 mg): (CDCl₃) δ 8.25 (d, J = 5.8 Hz, 2H), 8.04-7.89(m, 4H), 7.54 (d, J = 5.8 Hz, 2H), 7.39-7.29 (m, 4H), 5.97 (s, 2H),5.53-5.22 (m, 2H), 4.85 (ddd, J = 8.2, 4.4, 2.4 Hz, 2H), 4.55 (dd, J =9.3, 2.5 Hz, 2H), 4.39 (dd, J = 9.4, 8.3 Hz, 2H), 4.12-3.97 (m, 0H),3.76 (d, J = 62.5 Hz, 2H), 3.51 (s, 2H), 3.03 (s, 2H), 2.72 (q, J = 7.6Hz, 4H), 1.98-1.71 (m, 1H), 1.45-1.13 (m, 10H), 1.12-0.80 (m, 7H).HRMS(B) m/z 424.1859. RT = 2.40 min. Chiral RT = 3.25 min 174 and 175:Chiral separation was achieved by chiral SFC column(4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column AD-H 21 × 250mm 25% IPA in ((1-(3-(4-(trifluoromethyl)phenyl)- CO₂, flow 75 g/min,238 nm UV collection) to give (R)-4- 1,2,4-oxadiazol-5-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(4- yl)ethyl)amino)pyrimidin-4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5- yl)oxazolidin-2-oneyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 174: First eluted product(55 mg): (CDCl₃) δ 8.30-8.14 (m, 3H), 7.76 (dd, J = 8.7, 2.5 Hz, 2H),7.55 (dd, J = 12.4, 5.8 Hz, 1H), 6.61 (s, 1H), 5.32 (s, 1H), 4.77-4.62(m, 1H), 4.62-4.46 (m, 1H), 4.40 (t, J = 8.8 Hz, 1H), 4.24 (t, J = 9.0Hz, 1H), 3.51 (s, 1H), 1.81 (s, 2H), 1.22 (dd, J = 9.6, 6.3 Hz, 4H).HRMS(B) m/z 464.1420. RT = 2.43 min. Chiral RT = 2.55 min 175: Secondeluted product (51 mg): (CDCl₃) δ 8.22 (dd, J = 21.0, 7.0 Hz, 3H), 7.75(d, J = 8.1 Hz, 2H), 7.56 (d, J = 5.8 Hz, 1H), 6.47 (s, 1H), 5.37 (d, J= 39.2 Hz, 1H), 4.86 (ddd, J = 8.7, 4.7, 2.5 Hz, 1H), 4.55 (dd, J = 9.3,2.5 Hz, 1H), 4.40 (t, J = 8.9 Hz, 1H), 4.19-3.70 (m, 1H), 3.50 (s, 1H),2.01-1.70 (m, 0H), 1.23 (d, J = 6.1 Hz, 1H), 1.01 (s, 3H). HRMS(B) m/z464.1420. RT = 2.44 min. Chiral RT = 3.25 min 176 and 177: Chiralseparation was achieved by chiral SFC column(4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column AD-H 21 × 250mm 15% IPA in ((1-(3-phenethyl-1,2,4-oxadiazol- CO₂, flow 80 g/min, 238nm UV collection) to give (R)-4- 5-yl)ethyl)amino)pyrimidin-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-phenethyl-1,2,4-yl)oxazolidin-2-oneoxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-phenethyl-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin- 2-one 176:First eluted product (17 mg): (CDCl₃) δ 8.25 (d, J = 6.2 Hz, 1H), 7.54(d, J = 5.5 Hz, 1H), 7.36-7.07 (m, 5H), 5.83 (s, 1H), 5.10 (s, 1H), 4.67(d, J = 7.6 Hz, 1H), 4.57- 4.41 (m, 1H), 4.10 (d, J = 38.8 Hz, 2H),3.36-3.14 (m, 1H), 3.07 (d, J = 2.1 Hz, 4H), 1.94-1.67 (m, 1H), 1.28 (d,J = 3.8 Hz, 1H), 1.18 (d, J = 6.5 Hz, 3H). HRMS(B) m/z 424.1859. RT =2.24 min. Chiral RT = 4.50 min 177: Second eluted product (19 mg):(CDCl₃) δ 8.25 (d, J = 5.9 Hz, 1H), 7.56 (d, J = 5.7 Hz, 1H), 7.38-7.08(m, 5H), 6.03 (s, 1H), 5.31 (d, J = 11.3 Hz, 1H), 4.84 (ddd, J = 8.3,4.5, 2.3 Hz, 1H), 4.56 (dd, J = 9.3, 2.5 Hz, 1H), 4.40 (dd, J = 9.3, 8.3Hz, 1H), 3.91-3.62 (m, 1H), 3.51 (s, 2H), 3.36- 3.10 (m, 1H), 3.06 (s,4H), 1.72 (d, J = 7.0 Hz, 3H), 1.59- 1.35 (m, 1H), 1.06 (d, J = 6.8 Hz,3H). ). HRMS(B) m/z 424.1859. RT = 2.30 min. Chiral RT = 5.90 min 178and 179: Chiral separation was achieved by chiral SFC column(4R)-3-(2-((1-(3-(4-chloro-3- chromatography (Column AD-H 21 × 250 mm20% IPA in (trifluoromethoxy)phenyl)-1,2,4- CO₂, flow 75 g/min, 238 nmUV collection) to give (R)-3-(2- oxadiazol-5-yl)ethyl)amino)-5-(((R)-1-(3-(4-chloro-3-(trifluoromethoxy)phenyl)-1,2,4-fluoropyrimidin-4-yl)-4-((R)-1-oxadiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one hydroxyethyl)oxazolidin-2-one and(R)-3-(2-(((S)-1-(3-(4-chloro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 178: First eluted product (49 mg): (CDCl₃)δ 8.26 (d, J = 2.8 Hz, 1H), 8.05 (p, J = 1.4 Hz, 1H), 8.03-7.92 (m, 1H),7.62 (d, J = 8.4 Hz, 1H), 5.73 (d, J = 7.6 Hz, 1H), 5.44-5.25 (m, 1H),4.60-4.40 (m, 3H), 4.32 (p, J = 5.7, 5.3 Hz, 1H), 2.81- 1.89 (m, 2H),1.80 (s, 3H), 1.22 (d, J = 6.3 Hz, 3H). ). HRMS(B) m/z 533.1171. RT =2.64 min. Chiral RT = 3.05 min 179: Second eluted product (81 mg):(CDCl₃) δ 8.27 (d, J = 2.7 Hz, 1H), 8.04 (p, J = 1.4 Hz, 1H), 7.97 (dd,J = 8.4, 1.9 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 5.68 (t, J = 4.0 Hz,1H), 5.33 (s, 1H), 4.68 (dt, J = 10.9, 4.6 Hz, 1H), 4.56 (t, J = 9.0 Hz,1H), 4.44 (dd, J = 9.2, 5.3 Hz, 1H), 3.85 (s, 1H), 1.95 (d, J = 7.0 Hz,2H), 1.84-1.73 (m, 3H), 1.36-1.19 (m, 1H), 1.08 (s, 3H). HRMS(B) m/z533.1173. RT = 2.64 min. Chiral RT = 3.75 min 180 and 181: Chiralseparation was achieved by chiral SFC column(4R)-4-((R)-1-hydroxyethyl)-3-(2- chromatography (Column AD-H 21 × 250mm 25% IPA in ((1-(3-(4- CO₂, flow 80 g/min, 238 nm UV collection) to(R)-4-((R)-1- (trifluoromethoxy)phenyl)-1,2,4-hydroxyethyl)-3-(2-(((R)-1-(3-(4-(trifluoromethoxy)phenyl)- oxadiazol-5-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-yl)ethyl)amino)pyrimidin-4- 2-one and(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4- yl)oxazolidin-2-one(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 180: First eluted product(19 mg): (CDCl₃) δ 8.24 (d, J = 5.8 Hz, 1H), 8.16-8.06 (m, 2H), 7.53 (d,J = 5.8 Hz, 1H), 7.34 (d, J = 8.3 Hz, 2H), 6.24 (s, 1H), 5.29 (d, J =24.7 Hz, 1H), 4.81-4.61 (m, 1H), 1.85-1.74 (m, 3H), 4.51 (dd, J = 9.4,2.4 Hz, 1H), 4.46-4.32 (m, 1H), 4.31-4.13 (m, 1H), 3.51 (s, 1H), 3.25(d, J = 66.2 Hz, 1H), 1.22 (dd, J = 8.9, 6.3 Hz, 4H). HRMS(B) m/z480.1369. RT = 2.50 min. Chiral RT = 2.20 min 181: Second eluted product(44 mg): (CDCl₃) δ 8.25 (d, J = 5.8 Hz, 1H), 8.17-8.05 (m, 2H), 7.55 (d,J = 5.7 Hz, 1H), 7.33 (d, J = 8.3 Hz, 2H), 6.41 (s, 1H), 5.35 (d, J =27.1 Hz, 1H), 4.96-4.77 (m, 1H), 4.55 (dd, J = 9.3, 2.5 Hz, 1H), 4.40(t, J = 8.9 Hz, 1H), 4.16-3.55 (m, 1H), 3.03 (s, 1H), 1.78 (d, J = 7.1Hz, 3H), 1.23 (d, J = 6.1 Hz, 1H), 1.01 (s, 3H). HRMS(B) m/z 480.1369.RT = 2.51 min. Chiral RT = 2.45 min 182 and 183: Chiral separation wasachieved by chiral SFC column (4R)-4-((R)-1-hydroxyethyl)-3-(2-chromatography (Column AD-H 21 × 250 mm 30% IPA in ((1-(3-(3-(2,2,2-CO₂, flow 75 g/min, 238 nm UV collection) to give (R)-4-trifluoroethoxy)phenyl)-1,2,4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(3-(2,2,2- oxadiazol-5-trifluoroethoxy)phenyl)-1,2,4-oxadiazol-5- yl)ethyl)amino)pyrimidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-yl)oxazolidin-2-one ((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(3-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 182: First eluted product(13.8 mg): (CDCl₃) δ 8.14 (d, J = 5.9 Hz, 1H), 7.67 (t, J = 6.8 Hz, 1H),7.60-7.52 (m, 1H), 7.46 (dd, J = 14.2, 5.8 Hz, 1H), 7.37 (td, J = 8.0,2.8 Hz, 1H), 7.05 (dd, J = 8.2, 2.7 Hz, 1H), 4.71-4.51 (m, 1H),4.51-4.23 (m, 4H), 4.23-4.04 (m, 1H), 3.97 (hept, J = 6.1 Hz, 1H), 1.64(d, J = 1.5 Hz, 3H), 1.13 (dd, J = 10.4, 6.3 Hz, 6H). HRMS(B) m/z494.1526. RT = 2.38 min. Chiral RT = 1.95 min 183: Second eluted product(65 mg): (CDCl₃) δ 8.25 (d, J = 5.8 Hz, 1H), 7.77 (dt, J = 7.7, 1.2 Hz,1H), 7.63 (dd, J = 2.7, 1.4 Hz, 1H), 7.56 (d, J = 5.7 Hz, 1H), 7.45 (t,J = 8.0 Hz, 1H), 7.14 (ddd, J = 8.3, 2.7, 1.0 Hz, 1H), 6.06 (s, 1H),5.35 (d, J = 24.3 Hz, 1H), 4.85 (ddd, J = 8.3, 4.5, 2.5 Hz, 1H), 4.55(dd, J = 9.3, 2.5 Hz, 1H), 4.51-4.34 (m, 4H), 4.05 (hept, J = 6.1 Hz,1H), 3.89 (s, 1H), 2.96 (s, 1H), 1.84- 1.75 (m, 3H), 1.23 (d, J = 6.2Hz, 6H), 1.02 (s, 3H). HRMS(B) m/z 494.1526. RT = 2.39 min. Chiral RT =2.45 min 184 and 185: Chiral separation was achieved by chiral SFCcolumn (4R)-3-(2-((1-(5-(4- chromatography (Column AD-H 21 × 250 mm 20%MeOH in chlorophenyl)-4-methyloxazol-2- CO₂, flow 80 g/min, 238 nm UVcollection) to give (R)-3-(2- yl)ethyl)amino)pyrimidin-4-yl)-4-(((R)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 184: First eluted product (48mg): (CDCl₃) δ 8.21 (d, J = 5.7 Hz, 1H), 7.58-7.35 (m, 5H), 5.94 (s,1H), 4.62 (dd, J = 9.2, 2.5 Hz, 1H), 4.55-4.42 (m, 1H), 1.74-1.65 (m,3H), 4.32 (t, J = 8.9 Hz, 1H), 3.51 (s, 2H), 2.38 (s, 3H), 2.27- 1.93(m, 1H), 1.22 (d, J = 6.6 Hz, 3H). HRMS(B) m/z 443.1360. RT = 2.51 min.Chiral RT = 2.90 min 185: Second eluted product (31 mg): (CDCl₃) δ7.61-7.47 (m, 3H), 7.45-7.35 (m, 2H), 5.84 (s, 1H), 5.31 (d, J = 10.0Hz, 1H), 4.94 (s, 1H), 4.58 (d, J = 9.8 Hz, 2H), 1.78-1.66 (m, 3H), 4.44(t, J = 8.8 Hz, 1H), 4.22 (s, 1H), 3.52 (s, 2H), 2.38 (s, 3H), 1.16 (d,J = 6.4 Hz, 3H). HRMS(B) m/z 443.1360. RT = 2.52 min. Chiral RT = 4.00min 186 and 187: Chiral separation was achieved by chiral SFC column(4R)-3-(2-((1-(5-(4- chromatography (Column AD-H 21 × 250 mm 30% IPA inchlorophenyl)-4-methyloxazol-2- CO₂, flow 75 g/min, 238 nm UVcollection) to give (R)-3-(2- yl)ethyl)amino)-5-(((R)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-fluoropyrimidin-4-yl)-4-((R)-1-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one hydroxyethyl)oxazolidin-2-one and(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 186: Firsteluted product (114 mg): (MeOD) δ 8.14 (dd, J = 111.8, 3.1 Hz, 1H),7.64-7.53 (m, 2H), 7.53-7.42 (m, 2H), 5.35-5.18 (m, 1H), 5.18-5.05 (m,1H), 4.80-4.70 (m, 1H), 4.55-4.45 (m, 2H), 4.17 (td, J = 6.7, 3.9 Hz,1H), 4.07 (dt, J = 8.9, 5.4 Hz, 1H), 2.38 (d, J = 1.9 Hz, 3H), 1.67 (dd,J = 7.1, 5.4 Hz, 3H), 1.14 (dd, J = 27.1, 6.3 Hz, 3H). HRMS(B) m/z461.1266. RT = 2.29 min. Chiral RT = 3.60 min 187: Second eluted product(14 mg): (MeOD) δ 8.14 (dd, J = 115.3, 3.2 Hz, 1H), 7.59 (ddt, J = 6.7,4.3, 2.1 Hz, 2H), 7.53-7.42 (m, 2H), 5.14 (dq, J = 30.9, 6.9 Hz, 1H),4.71 (dt, J = 9.6, 4.6 Hz, 1H), 4.39 (q, J = 7.4, 5.0 Hz, 1H), 3.98(ddt, J = 28.7, 12.3, 5.6 Hz, 2H), 2.37 (d, J = 2.3 Hz, 3H), 1.67 (dd, J= 7.1, 4.0 Hz, 3H), 1.32 (d, J = 6.5 Hz, 2H), 1.17 (d, J = 6.1 Hz, 2H),1.08-0.76 (m, 2H). HRMS(B) m/z 461.1266. RT = 2.37 min. Chiral RT = 6.05min 188 and 189: Chiral separation was achieved by chiral SFC column(4R)-3-(2-((1-(4-(4- chromatography (Column ID 21 × 250 mm 25% MeOH 10chlorophenyl)-5-methylthiazol-2- mM NH4OH in CO₂, flow 75 g/min, 230 nmUV collection) yl)ethyl)amino)-5- to give(R)-3-(2-(((R)-1-(4-(4-chlorophenyl)-5-methylthiazol-fluoropyrimidin-4-yl)-4-((R)-1-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one hydroxyethyl)oxazolidin-2-one and(R)-3-(2-(((S)-1-(4-(4-chlorophenyl)-5-methylthiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 188: Firsteluted product (61.8 mg): ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J = 3.2 Hz,1H), 7.64-7.53 (m, 2H), 7.49- 7.38 (m, 2H), 5.75 (d, J = 6.1 Hz, 1H),5.22 (s, 1H), 4.54- 4.24 (m, 4H), 3.49 (s, 2H), 2.52 (s, 3H), 1.17 (d, J= 6.4 Hz, 3H). HRMS(E) m/z 478.1114 (M + H). RT = 5.98 min. Chiral RT =3.90 min. 189: Second eluted product (82 mg): ¹H NMR (400 MHz, CDCl₃) δ8.32-7.93 (m, 1H), 7.68-7.52 (m, 2H), 7.43 (dd, J = 8.6, 2.5 Hz, 2H),5.75 (d, J = 6.8 Hz, 1H), 5.35- 5.21 (m, 1H), 4.58 (dt, J = 8.6, 5.3 Hz,1H), 1.77-1.64 (m, 3H), 4.53-4.43 (m, 1H), 4.38 (dd, J = 9.0, 5.0 Hz,1H), 3.96 (d, J = 11.1 Hz, 1H), 3.50 (s, 2H), 2.52 (d, J = 6.1 Hz, 3H),1.04 (d, J = 49.6 Hz, 3H). HRMS(B) m/z 477.1038. RT = 2.48 min. ChiralRT = 5.80 min. 190 and 191: Chiral separation was achieved by chiral SFCcolumn (4R)-3-(2-((1-(4-(4- chromatography (Column ID 21 × 250 mm 30%MeOH 10 bromophenyl)thiazol-2- mM NH4OH in CO₂, flow 75 g/min, 230 nm UVcollection) yl)ethyl)amino)-5- to give(R)-3-(2-(((S)-1-(4-(4-bromophenyl)thiazol-2-fluoropyrimidin-4-yl)-4-((R)-1-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one hydroxyethyl)oxazolidin-2-one and(R)-3-(2-(((R)-1-(4-(4-bromophenyl)thiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 190: First eluted product(63.7 mg): ¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J = 3.0 Hz, 1H), 7.86-7.71(m, 2H), 7.62- 7.50 (m, 2H), 7.41 (s, 1H), 5.80 (d, J = 6.7 Hz, 1H),1.83- 1.68 (m, 3H), 5.33 (t, J = 5.2 Hz, 1H), 4.38 (t, J = 13.2 Hz, 4H),3.51 (s, 1H), 1.20 (d, J = 6.2 Hz, 3H). HRMS(E) m/z 510.0447 (M + H). RT= 5.95 min. Chiral RT = 3.30 min. 191: Second eluted product (77.1): ¹HNMR (400 MHz, CDCl₃) δ 8.13 (dd, J = 109.6, 2.8 Hz, 1H), 7.78 (dd, J =8.6, 2.1 Hz, 2H), 7.57 (dd, J = 8.8, 2.3 Hz, 2H), 7.40 (s, 1H), 5.78 (d,J = 6.5 Hz, 1H), 1.82-1.67 (m, 3H), 5.46-5.24 (m, 1H), 4.64-4.26 (m,2H), 4.05-3.74 (m, 1H), 3.51 (s, 1H), 0.96 (s, 3H). HRMS(E) m/z 510.0445(M + H). RT = 5.91 min. Chiral RT = 5.40 min. 192 and 193: Chiralseparation was achieved by chiral SFC column (R)-3-(2-((1-(5-(3,4-chromatography (Column IC 21 × 250 mm, 45% MeOH indichlorophenyl)pyrimidin-2- CO2, flow 75 g/min, 220 nm UV collection) togive (R)-3-(2- yl)ethyl)amino)-5-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-onehydroxyethyl)oxazolidin-2-one and(R)-3-(2-(((R)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one. 192: First eluted product (49 mg ¹H NMR(400 MHz, CDCl₃) δ 8.88 (s, 2H), 8.24 (d, J = 2.8 Hz, 1H), 7.76-7.51 (m,2H), 7.48-7.35 (m, 1H), 6.17 (d, J = 7.9 Hz, 1H), 5.30 (tt, J = 12.5,5.8 Hz, 1H), 4.69-4.47 (m, 2H), 4.41 (dd, J = 8.9, 5.1 Hz, 1H), 4.09 (brs, 1H), 1.69-1.65 (m, 3H), 1.15 (d, J = 6.2 Hz, 3H). HRMS(B) m/z493.0948 (M + H)⁺. 193: Second eluted product (40 mg) ¹H NMR (400 MHz,CDCl₃) δ 8.89 (d, J = 1.6 Hz, 2H), 8.25 (d, J = 2.9 Hz, 1H), 7.76-7.53(m, 2H), 7.43 (ddd, J = 8.3, 3.9, 2.2 Hz, 1H), 6.24 (d, J = 7.5 Hz, 1H),5.26 (br s, 1H), 4.60-4.36 (m, 4H), 1.64 (d, J = 4.8 Hz, 2H), 1.29-1.25(m, 3H). HRMS(B) m/z 493.0949 (M + H)⁺. 194 and 195: Chiral separationwas achieved by chiral SFC column (R)-4-((R)-1-hydroxyethyl)-3-(2-chromatography (Column IA 21 × 250 mm, 35% IPA 10 mM ((1-(5-(3-methyl-4-NH4OH in CO2, flow 75 g/min, 235 nm UV collection) to(trifluoromethyl)phenyl)pyrimidin- give(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-methyl-4-2-yl)ethyl)amino)pyrimidin-4-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-yl)oxazolidin-2-one 4-yl)oxazolidin-2-one and(R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(5-(3-methyl-4-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one. 194: First elutedproduct (15 mg) ¹H NMR (400 MHz, CDCl₃) δ 8.95 (s, 2H), 8.23 (d, J = 5.7Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.54-7.42 (m, 4H), 6.07 (d, J = 8.2Hz, 1H), 5.45-5.36 (m, 1H), 4.89 (s, 1H), 4.52 (dd, J = 9.5, 2.6 Hz,1H), 4.42 (dd, J = 9.4, 8.3 Hz, 1H), 3.36 (br s, 1H), 2.60 (dq, J = 3.7,1.7 Hz, 3H), 1.71-1.60 (m, 3H), 1.11 (br s, 3H). HRMS(D) m/z 489.1850(M + H)⁺. 195: Second eluted product (11 mg) ¹H NMR (400 MHz, CDCl₃) δ8.94 (s, 2H), 8.23 (d, J = 5.7 Hz, 1H), 7.81-7.74 (m, 1H), 7.49 (d, J =6.9 Hz, 1H), 7.42 (d, J = 5.7 Hz, 1H), 6.02 (br s, 1H), 5.18 (br s, 1H),4.80 (br s, 1H), 4.53 (d, J = 8.8 Hz, 1H), 4.30 (br s, 2H), 3.71 (br s,1H), 2.60 (q, J = 1.8 Hz, 3H), 1.69-1.65 (m, 3H), 1.25-1.19 (m, 3H).HRMS(D) m/z 489.1862 (M + H)⁺. 196 and 197: Chiral separation wasachieved by chiral SFC column (R)-4-((R)-1-hydroxyethyl)-3-(2-chromatography (Column IC 21 × 250 mm, 30% IPA 10 mM((1-(4-methyl-5-(2-(1,1,1- NH4OH in CO2, flow 75 g/min, 227 nm UVcollection) to trifluoro-2-methylpropan-2- give(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-5-(2-yl)pyridin-4-yl)thiazol-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-yl)oxazolidin-2-one((R)-1-hydroxyethyl)-3-(2-(((R)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one. 198: First elutedproduct (50 mg) ¹H NMR (400 MHz, CDCl₃) δ 8.65 (dd, J = 5.1, 0.8 Hz,1H), 8.26 (d, J = 5.8 Hz, 1H), 7.59-7.49 (m, 2H), 7.24 (dd, J = 5.2, 1.6Hz, 1H), 5.63 (d, J = 6.4 Hz, 1H), 5.38 (s, 1H), 4.80 (ddd, J = 8.3,4.5, 2.5 Hz, 1H), 4.51 (dd, J = 9.4, 2.5 Hz, 1H), 4.40 (dd, J = 9.4, 8.3Hz, 1H), 3.93 (br s, 1H), 2.79 (br s, 1H), 2.54 (s, 3H), 1.73 (d, J =7.0 Hz, 3H), 1.67 (s, 6H), 1.05 (d, J = 6.9 Hz, 3H). HRMS(D) m/z537.1898 (M + H)⁺. 199: Second eluted product (50 mg) ¹H NMR (400 MHz,CDCl₃) δ 8.65 (dd, J = 5.2, 0.8 Hz, 1H), 8.25 (d, J = 5.8 Hz, 1H),7.59-7.46 (m, 2H), 7.26 (dd, J = 5.1, 1.6 Hz, 1H), 5.69 (s, 1H), 5.13(br s, 1H), 4.82 (br s, 1H), 4.58 (d, J = 6.7 Hz, 1H), 4.31 (t, J = 8.4Hz, 2H), 4.15 (br s, 1H), 2.53 (s, 3H), 1.76-1.65 (m, 9H), 1.25-1.18 (m,3H). HRMS(D) m/z 537.1900(M + H)⁺. 198 and 199: Chiral separation wasachieved by chiral SFC column (4R)-3-(5-fluoro-2-((1-(4-methyl-chromatography (Column ID 21 × 250 mm, 25% IPA 10 mM5-(2-(1,1,1-trifluoro-2- NH4OH in CO2, flow 75 g/min, 230 nm UVcollection) to methylpropan-2-yl)pyridin-4-yl)thiazol-2- giveyl)ethyl)amino)pyrimidin-4-yl)-4-(4R)-3-(5-fluoro-2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-((R)-1-hydroxyethyl)oxazolidin-methylpropan-2-yl)pyridin-4-yl)thiazol-2- 2-oneyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-oneand (4R)-3-(5-fluoro-2-(((R)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one. 200: First eluted product (7 mg)¹H NMR (400 MHz, CDCl₃) δ 8.55 (td, J = 5.4, 0.8 Hz, 1H), 8.17 (dd, J =4.5, 2.8 Hz, 1H), 7.46-7.40 (m, 1H), 7.16 (ddd, J = 8.1, 5.1, 1.6 Hz,1H), 5.56 (dd, J = 14.8, 6.8 Hz, 1H), 5.20-5.13 (m, 1H), 4.49-4.37 (m,2H), 4.30 (d, J = 6.8 Hz, 1H), 3.32 (d, J = 3.7 Hz, 1H), 2.46 (s, 3H),1.67-1.50 (m, 9H), 1.18-1.12 (m, 3H). HRMS(D) m/z 555.1821 (M + H)⁺.201: Second eluted product (33 mg) ¹H NMR (400 MHz, CDCl₃) δ 8.60-8.52(m, 1H), 8.17 (d, J = 2.8 Hz, 1H), 7.42 (dt, J = 1.7, 0.8 Hz, 1H),7.21-7.12 (m, 1H), 5.56 (d, J = 6.9 Hz, 1H), 5.24 (p, J = 7.0 Hz, 1H),4.55 (dt, J = 8.6, 5.5 Hz, 1H), 4.45 (t, J = 8.8 Hz, 1H), 4.31 (dd, J =9.0, 5.2 Hz, 1H), 3.95 (td, J = 13.7, 13.0, 6.9 Hz, 1H), 2.45 (s, 3H),1.64 (d, J = 6.9 Hz, 3H), 1.57 (s, 6H), 1.00 (d, J = 6.0 Hz, 3H).HRMS(D) m/z 555.1839 (M + H)⁺. 200 and 201: Chiral separation wasachieved by chiral SFC column (R)-3-(2-((1-(5-(2-fluoro-3-chromatography (Column IA 21 × 250 mm, 25% MeOH(trifluoromethyl)phenyl)pyrimidin- 10 mM NH4OH in CO2, flow 75 g/min,232 nm UV 2-yl)ethyl)amino)pyrimidin-4-yl)- collection) to give(R)-3-(2-(((S)-1-(5-(2-fluoro-3- 4-((R)-1-hydroxyethyl)oxazolidin-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin- 2-one4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((R)-1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one.192: First eluted product (35 mg) ¹H NMR (400 MHz, CDCl₃) δ 8.85-8.79(m, 2H), 8.12 (dd, J = 6.1, 4.0 Hz, 1H), 7.70-7.52 (m, 2H), 7.41-7.30(m, 2H), 6.14 (s, 1H), 5.36-5.27 (m, 1H), 4.85-4.76 (m, 1H), 4.43 (dd, J= 9.4, 2.6 Hz, 1H), 4.38-4.24 (m, 1H), 4.13-3.93 (m, 1H), 3.15 (br s,1H), 1.60 (d, J = 7.0 Hz, 3H), 1.02 (br s, 3H). HRMS(D) m/z 493.1605(M + H)⁺. 193: Second eluted product (36 mg) ¹H NMR (400 MHz, CDCl₃) δ8.83 (d, J = 1.4 Hz, 2H), 8.12 (d, J = 5.8 Hz, 1H), 7.71-7.53 (m, 2H),7.42-7.31 (m, 2H), 6.19 (br s, 1H), 5.08 (br s, 1H), 4.68 (br s, 1H),4.46 (d, J = 8.3 Hz, 1H), 4.21 (br s, 2H), 3.50 (br s, 1H), 1.60 (d, J =7.0 Hz, 3H), 1.19-1.12 (m, 3H). HRMS(D) m/z 493.1630 (M + H)⁺.

Examples 202 and 203(4R)-3-(2-((1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one(124 mg, 0.246 mmol) was treated with 90% TFA/water for 2 hours.Concentrated in vacuo and neutralized by passing through a column ofMP-carbonate resin (2.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOHafforded the diastereomeric mixture. Chiral SFC chromatography on an IDcolumn (75 g/min, 120 bar, 21×250 mm) eluting 45% IPA/CO₂ (v/v) to give(R)-3-(2-(((R)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-oneand(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.

202: Peak 1: 15 mg (pale orange foam): (CDCl₃) δ 8.22 (d, J=3.2 Hz, 1H),7.63-7.50 (m, 2H), 7.45-7.38 (m, 2H), 7.28 (s, 1H), 5.65 (d, J=7.0 Hz,1H), 5.16 (s, 1H), 4.80-4.25 (m, 3H), 3.51 (s, 1H), 1.71 (d, J=7.0 Hz,3H), 1.38-1.15 (m, 4H). HRMS(B) m/z 447.1110. RT=2.20 min.

203: Peak 2: 87 mg (pale orange foam): (CDCl₃) δ 8.24 (d, J=2.9 Hz, 1H),7.59-7.49 (m, 2H), 7.46-7.37 (m, 2H), 7.24-7.18 (m, 1H), 5.66 (d, J=8.1Hz, 1H), 5.32 (dd, J=8.3, 6.6 Hz, 1H), 4.79 (s, 1H), 4.56 (t, J=8.9 Hz,1H), 4.39 (dd, J=9.1, 5.7 Hz, 1H), 4.04 (td, J=11.0, 9.7, 4.8 Hz, 1H),3.51 (s, 1H), 1.70 (s, 1H), 1.23 (d, J=6.2 Hz, 2H), 1.16 (d, J=6.4 Hz,3H). HRMS(B) m/z 447.1110. RT=2.20 min.

Examples 204 and 205(4R)-3-(2-((1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one(3.50 g, 2.88 mmol) was treated with 90% TFA/water for 2 hours.Concentrated in vacuo and neutralized by passing through a column ofMP-carbonate resin (6.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOHafforded the diastereomeric mixture. Chiral SFC chromatography on anOJ-H column (75 g/min, 120 bar, 21×250 mm) eluting 30% IPA+10 mMNH4OH/CO₂ (v/v) to give(R)-3-(2-(((S)-1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-oneand(R)-3-(2-(((R)-1-(3-(4-chlorophenyl)isoxazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one.

204: Peak 1: 1.40 g (white powder crystals): ¹H NMR (400 MHz, CDCl₃) δ8.22 (d, J=5.8 Hz, 1H), 7.76-7.63 (m, 2H), 7.54 (d, J=5.7 Hz, 1H),7.50-7.37 (m, 2H), 6.46 (s, 1H), 5.90-5.55 (m, 1H), 5.27-5.04 (m, 1H),4.93-4.79 (m, 1H), 4.56 (dd, J=9.3, 2.5 Hz, 1H), 4.40 (dd, J=9.4, 8.4Hz, 1H), 3.51 (s, 2H), 3.25 (d, J=68.4 Hz, 1H), 1.98-1.55 (m, 2H), 0.91(s, 3H). HRMS(B) m/z 429.1204. RT=2.45 min.

205: Peak 2: 1.35 g (off-white foam): ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d,J=6.0 Hz, 1H), 7.79-7.64 (m, 2H), 7.54 (d, J=5.8 Hz, 1H), 7.49-7.37 (m,2H), 6.47 (s, 1H), 5.77 (s, 1H), 1.80-1.61 (m, 4H), 5.16 (s, 1H),4.71-4.45 (m, 2H), 4.46-4.22 (m, 2H), 3.51 (s, 2H), 2.87 (s, 1H), 1.20(d, J=6.5 Hz, 4H). HRMS(B) m/z 429.1204. RT=2.45 min.

Example 206(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one(360 mg, 0.741 mg) was treated with 90% TFA/water for 2 hours.Concentrated in vacuo and neutralized by passing through a column ofMP-carbonate resin (2.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOHafforded the desired product (120 mg, pale yellow foam). ¹H NMR (400MHz, CDCl₃) δ 8.15 (d, J=6.0 Hz, 1H), 7.64-7.49 (m, 3H), 7.49-7.35 (m,2H), 7.29 (s, 1H), 5.33 (dd, J=9.4, 5.1 Hz, 1H), 5.04-4.81 (m, 1H),1.80-1.69 (m, 3H), 4.71-4.53 (m, 1H), 4.45 (dd, J=9.4, 8.1 Hz, 1H),4.28-3.97 (m, 1H), 3.51 (s, 3H), 1.14 (d, J=6.4 Hz, 3H). HRMS(B) m/z429.1204. RT=2.22 min.

Example 207:(R)-3-(6-chloro-2-((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

Trifluoroacetic acid (2 mL) was added to a solution of(R)-4-((R)-1-tert-butoxyethyl)-3-(6-chloro-2-((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one(25.0 mg, 0.039 mmol), in DCM (2 mL) and the solution was stirred atroom temperature for 1 h. The reaction mixture was then concentrated andpurification by reverse phase HPLC provided the trifluoroacetate salt of(R)-3-(6-chloro-2-((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one(10.0 mg, white solid) in 44% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d,J=8.4 Hz, 2H), 7.63 (s, 1H), 7.48 (d, J=8.4 Hz, 2H), 5.30 (br m, 1H),4.80-4.77 (m, 1H), 4.55-4.52 (m, 1H), 4.41-4.36 (m, 1H), 3.77-3.62 (brm, 1H), 1.78 (d, J=7.1 Hz, 3H), 0.95 (br m, 3H); HRMS m/z 465.0847(M+H)⁺; Rt-2.25 min.

The compounds in Table 30a were prepared using methods similar to thosedescribed for the preparation of Examples 35, 36, 37/38, or 207.

TABLE 30a

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

TABLE 30b Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 30a. Example: Name ¹H NMR (400 MHz, CDCl₃) δppm LCMS 208: (R)-3-(6-chloro-2- 7.59 (s, 1H), 7.52-7.48 (m, 1H), 7.44-HRMS m/z ((S)-1-(2-fluoro-4- 7.42 (m, 1H), 7.37 (d, J = 9.7 Hz, 1H),5.31 449.1009 (trifluoromethyl)phenyl)ethyl- (br m, 1H), 4.68-4.66 (m,1H), 4.49- (M + H)⁺; amino)pyrimidin-4-yl)-4-((R)-1- 4.46 (m, 1H),4.38-4.34 (m, 1H), 3.43 (br Rt-2.39 min hydroxyethyl)oxazolidin-2- m,1H), 1.59 (d, J = 7.0 Hz, 3H), 0.83 (br one m, 3H) 209:(R)-3-(6-chloro-2- 7.77 (s, 1H), 7.61 (s, 1H), 7.55 (s, 1H), HRMS m/z((S)-1-(2-fluoro-4-(1- 7.36-7.30 (m, 1H), 7.25-7.21 (m, 1H), 461.1505methyl-1H-pyrazol-4- 7.17 (dd, J = 11.4, 1.5 Hz, 1H), 5.26 (br m, (M +H)⁺; yl)phenyl)ethylamino)pyrim- 1H), 4.70 (ddd, J = 8.1, 5.2, 2.5 Hz,1H), Rt-2.00 idin-4-yl)-4-((R)-1- 4.45 (dd, J = 9.4, 2.5 Hz, 1H),4.39-4.31 hydroxyethyl)oxazolidin-2- (m, 1H), 3.98 (s, 3H), 3.67-3.55(m, 1H), one 1.57 (d, J = 6.9 Hz, 3H), 0.82 (br m, 3H) 210:(R)-3-(2-((S)-1-(3-(4- 8.00 (d, J = 8.6 Hz, 2H), 7.91 (s, 1H), 7.48 HRMSm/z chlorophenyl)-1,2,4- (d, J = 8.6 Hz, 2H), 6.45 (t, J = 56 Hz, 1H),481.1206 oxadiazol-5- 4.84 (m, 1H), 4.83 (dt, J = 5.3, 2.5 Hz, 1H), (M +H)⁺; yl)ethylamino)-6- 4.57 (d, J = 9.0 Hz, 1H), 4.46-4.37 (m, Rt-2.32(difluoromethyl)pyrimidin- 1H), 3.69 (m, 1H), 1.83 (d, J = 7.0 Hz, 3H),4-yl)-4-((R)-1- 0.96 (br m, 3H) hydroxyethyl)oxazolidin-2- one 211:(R)-3-(2-((S)-1-(3-(4- 8.00 (d, J = 8.6 Hz, 2H), 7.93 (s, 1H), 7.48 HRMSm/z chlorophenyl)-1,2,4- (d, J = 8.6 Hz, 2H), 5.31 (br. s., 1 H), 4.90-499.1106 oxadiazol-5- 4.80 (m, 1H), 4.57 (dd, J = 9.6, 1.8 Hz, (M + H)⁺;yl)ethylamino)-6- 1H), 4.48-4.35 (m, 1H), 3.74 (br m, 1H), Rt-2.50(trifluoromethyl)pyrimidin- 1.81 (d, J = 7.1 Hz, 3H), 1.25-0.84 (br m,4-yl)-4-((R)-1- 3H) hydroxyethyl)oxazolidin-2- one 212:(R)-3-(6-chloro-2- 7.90 (s, 1H), 7.80 (s, 1H), 7.59 (br s, 1H), HRMS m/z(((S)-1-(2,5-difluoro-4-(1- 7.25-7.21 (m, 1H), 7.12 (dd, J = 11.0, 6.3479.1415 methyl-1H-pyrazol-4- Hz, 1H), 5.25 (br m, 1H), 4.72 (m, 1H),(M + H)⁺; yl)phenyl)ethyl)amino)pyrim- 4.49 (d, J = 9.4 Hz, 1H),4.43-4.33 (m, Rt-2.04 idin-4-yl)-4-((R)-1- 1H), 4.02 (s, 3H), 3.72 (brm, 1H), 1.58 (d, hydroxyethyl)oxazolidin-2- J = 7.0 Hz, 3H), 0.88 (br s,3H) one 213: (R)-3-(6-chloro-2- 7.70 (d, J = 8.6 Hz, 2H), 7.60 (s, 1H),7.46 HRMS m/z (((S)-1-(5-(4- (d, J = 8.6 Hz, 2H), 6.54 (s, 1H), 5.23 (m,464.0894 chlorophenyl)isoxazol-3- 1H), 4.87 (m, 1H), 4.58 (d, J = 9.5Hz, 1H), (M + H)⁺; yl)ethyl)amino)pyrimidin-4- 4.47-4.39 (m, 1H), 3.89(m, 1H), 1.67 (d, Rt-2.38 yl)-4-((R)-1- J = 7.1 Hz, 3H), 1.05 (d, J =5.7 Hz, 3H) hydroxyethyl)oxazolidin-2- one 214: (R)-3-(6-chloro-2-7.78-7.73 (m, 2H), 7.59 (s, 1H), 7.50- HRMS m/z(((S)-1-(5-phenylisoxazol- 7.44 (m, 3H), 6.54 (s, 1H), 5.23 (m, 1H),430.1278 3-yl)ethyl)amino)pyrimidin- 4.87 (m, 1H), 4.58 (d, J = 9.5 Hz,1H), 4.42 (M + H)⁺; 4-yl)-4-((R)-1- (d, J = 9.3, 8.4 Hz, 1H), 3.89 (m,1H), 1.67 Rt-2.19 hydroxyethyl)oxazolidin-2- (d, J = 7.1 Hz, 3H), 1.05(d, J = 5.7 Hz, 3H) one 215: (R)-3-(6-fluoro-2- 7.80 (s, 1H), 7.73 (s,1H), 7.63-7.55 (m, HRMS m/z (((S)-1-(1-(4-fluorophenyl)- 2H), 7.19-7.10(m, 3H), 5.04 (m, 1H), 431.1644 1H-pyrazol-4- 4.72 (m, 1H), 4.47 (m,1H), 4.43-4.34 (m, (M + H)⁺; yl)ethyl)amino)pyrimidin-4- 1H), 3.73 (m,1H), 1.62 (d, J = 6.9 Hz, 3H), Rt-2.06 yl)-4-((R)-1- 0.97 (br m, 3H)hydroxyethyl)oxazolidin-2- one 216: (R)-3-(6-chloro-2- 7.95 (s, 1H),7.80 (d, J = 8.7 Hz, 2H), 7.65 HRMS m/z (((S)-1-(2-(4- (s, 1H), 7.48 (d,J = 8.7 Hz, 2H), 5.35 (m, 480.0666 chlorophenyl)thiazol-5- 1H), 4.80 (m,1H), 4.59 (d, J = 8.5 Hz, 1H), (M + H)⁺; yl)ethyl)amino)pyrimidin-4-4.40 (m, 1H), 3.72 (m, 1H), 1.74 (d, J = 6.9 Rt-2.46 yl)-4-((R)-1- Hz,3H), 0.97 (br s, 3H) hydroxyethyl)oxazolidin-2- one 217:(R)-3-(2-(((S)-1-(2-(4- 8.14 (d, J = 3.4 Hz, 1H), 7.93 (s, 1H), 7.79HRMS m/z chlorophenyl)thiazol-5- (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8Hz, 464.0964 yl)ethyl)amino)-5- 2H), 5.33 (m, 1H), 4.71 (m, 1H), 4.58(t, J = (M + H)⁺; fluoropyrimidin-4-yl)-4- 9.0 Hz, 1H), 4.48 (dd, J =9.3, 5.3 Hz, Rt-2.08 ((R)-1- 1H), 3.72 (m, 1H), 1.79 (d, J = 7.0 Hz,3H), hydroxyethyl)oxazolidin-2- 1.02 (d, J = 6.2 Hz, 3H) one 218:(R)-3-(2-(((S)-1-(5-(4- 8.07 (d, J = 3.8 Hz, 1H), 7.69 (d, J = 8.8 HRMSm/z chlorophenyl)isoxazol-3- Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 6.62 (s,448.1186 yl)ethyl)amino)-5- 1H), 5.31 (m, 1H), 4.95 (m, 1H), 4.62 (t, J= (M + H)⁺; fluoropyrimidin-4-yl)-4- 9.0 Hz, 1H), 4.43 (dd, J = 9.3, 5.4Hz, Rt-2.03 ((R)-1- 1H), 3.98-3.88 (m, 1H), 1.73 (d, J = 7.1hydroxyethyl)oxazolidin-2- Hz, 3H), 1.18 (d, J = 6.5 Hz, 3H) one 219:(R)-3-(6-chloro-2- 7.85 (d, J = 8.4 Hz, 2H), 7.65 (s, 1H), 7.48 HRMS m/z(((S)-1-(5-(4- (d, J = 8.4 Hz, 2H), 5.44 (m, 1H), 4.86 (m, 481.0618chlorophenyl)-1,3,4- 1H), 4.59 (d, J = 9.5 Hz, 1H), 4.40 (t, J = (M +H)⁺; thiadiazol-2- 8.9 Hz, 1H), 3.33 (m, 1H), 1.80 (d, J = 7.0 Rt-2.25yl)ethyl)amino)pyrimidin-4- Hz, 3H), 0.91 (br s, 3H) yl)-4-((R)-1-hydroxyethyl)oxazolidin-2- one 220: (R)-3-(6-chloro-2- 7.86 (s, 1H),7.79 (s, 1H), 7.60 (s, 1H), HRMS m/z (((S)-1-(1-(4- 7.56 (d, J = 9.0 Hz,2H), 7.44 (d, J = 9.0 463.1055 chlorophenyl)-1H-pyrazol- Hz, 2H), 5.03(m, 1H), 4.76 (m, 1H), 4.51 (M + H)⁺; 4-yl)ethyl)amino)pyrimidin- (m,1H), 4.45-4.33 (m, 1H), 3.75 (m, 1H), Rt-2.31 4-yl)-4-((R)-1- 1.63 (d, J= 6.9 Hz, 3H), 0.96 (br m, 3H) hydroxyethyl)oxazolidin-2- one 221:(R)-3-(2-(((S)-1-(1-(4- 8.24 (d, J = 2.7 Hz, 1H), 7.85 (s, 1H), 7.70HRMS m/z chlorophenyl)-1H-pyrazol- (s, 1H), 7.59 (d, J = 8.9 Hz, 2H),7.41 (d, J = 447.1350 4-yl)ethyl)amino)-5- 8.9 Hz, 2H), 5.34 (m, 1H),5.04 (m, 1H), (M + H)⁺; fluoropyrimidin-4-yl)-4- 4.57-4.48 (m, 2H),4.43-4.34 (m, 1H), Rt-1.98 ((R)-1- 3.84 (m, 1H), 1.61 (d, J = 6.9 Hz,3H), 1.08 hydroxyethyl)oxazolidin-2- (d, J = 6.2 Hz, 3H) one 222:(R)-3-(2-(((S)-1-(5-(4- 7.82 (s, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.46HRMS m/z chlorophenyl)isoxazol-3- (d, J = 8.5 Hz, 2H), 6.65 (s, 1H),5.46 (s, 462.1347 yl)ethyl)amino)-6- 1H), 5.36-5.29 (m, 2H), 4.96 (m,1H), (M + H)⁺; (fluoromethyl)pyrimidin-4- 4.62 (d, J = 9.0 Hz, 1H),4.53-4.45 (m, Rt-2.22 yl)-4-((R)-1- 1H), 3.99 (m, 1H), 1.73 (d, J = 7.2Hz, 3H), hydroxyethyl)oxazolidin-2- 1.13 (d, J = 6.6 Hz, 3H) one 223:(R)-3-(2-(((S)-1-(2-(4- 7.88 (s, 1H), 7.87 (s, 1H), 7.80 (d, J = 8.6HRMS m/z chlorophenyl)thiazol-5- Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 5.47(s, 478.1116 yl)ethyl)amino)-6- 1H), 5.38-5.30 (m, 2H), 4.86 (ddd, J =(M + H)⁺; (fluoromethyl)pyrimidin-4- 8.1, 4.3, 2.2 Hz, 1H), 4.69-4.62(m, 1H), Rt-2.28 yl)-4-((R)-1- 4.45 (dd, J = 9.5, 8.2 Hz, 1H), 3.61 (m,hydroxyethyl)oxazolidin-2- 1H), 1.80 (d, J = 7.0 Hz, 3H), 0.95 (d, J =one 6.4 Hz, 3H) 224: (R)-3-(2-(((S)-1-(2-(4- 7.99 (d, J = 7.1 Hz, 1H),7.93 (s, 1H), 7.85- HRMS m/z chlorophenyl)thiazol-5- 7.78 (m, 3H), 7.47(d, J = 8.7 Hz, 2H), 446.1065 yl)ethyl)amino)pyrimidin-4- 5.43-5.34 (m,1H), 4.89 (ddd, J = 8.1, (M + H)⁺; yl)-4-((R)-1- 4.1, 2.2 Hz, 1H), 4.69(dd, J = 9.4, 8.2 Hz, Rt-1.90 hydroxyethyl)oxazolidin-2- 1H), 3.69 (dd,J = 6.3, 4.4 Hz, 1H), 1.83 (d, one J = 7.0 Hz, 3H), 0.97 (d, J = 6.5 Hz,3H) 225: (R)-3-(2-(((S)-1-(1-(4- 10.64 (d, J = 5.9 Hz, 1H), 7.98 (s,1H), HRMS m/z chlorophenyl)-1H-pyrazol- 7.95 (d, J = 7.1 Hz, 1H),7.78-7.74 (m, 429.1441 4-yl)ethyl)amino)pyrimidin- 2H), 7.59 (d, J = 9.0Hz, 2H), 7.43 (d, J = (M + H)⁺; 4-yl)-4-((R)-1- 9.0 Hz, 2H), 5.06 (quin,J = 6.7 Hz, 1H), Rt-1.62 hydroxyethyl)oxazolidin-2- 4.84 (ddd, J = 8.2,4.4, 2.3 Hz, 1H), 4.62 one (dd, J = 9.6 2.3 Hz, 1H), 4.45 (dd, J = 9.5,8.2 Hz, 1H), 3.80-3.69 (m, 1H), 1.70 (d, J = 7.0 Hz, 3H), 0.96 (d, J =6.5 Hz, 3H) 226: (R)-3-(6-chloro-2- 7.70 (d, J = 8.6 Hz, 2H), 7.65 (s,1H), 7.45 HRMS m/z (((S)-1-(3-(4- (d, J = 8.6 Hz, 2H), 6.50 (s, 1H),5.09 (m, 464.0898 chlorophenyl)isoxazol-5- 1H), 4.87 (m, 1H), 4.59 (d, J= 9.1 Hz, 1H), (M + H)⁺; yl)ethyl)amino)pyrimidin-4- 4.46-4.37 (m, 1H),3.49 (m, 1H), 1.72 (d, Rt-2.37 yl)-4-((R)-1- J = 7.1 Hz, 3H), 0.89 (brs, 3H) hydroxyethyl)oxazolidin-2- one 227: (R)-3-(2-(((S)-1-(3-(4- 8.13(d, J = 3.5 Hz, 1H), 7.69 (d, J = 8.5 HRMS m/z chlorophenyl)isoxazol-5-Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 6.52 (s, 448.1190 yl)ethyl)amino)-5-1H), 5.17 (m, 1H), 4.94 (m, 1H), 4.64- (M + H)⁺;fluoropyrimidin-4-yl)-4- 4.57 (m, 1H), 4.52 (dd, J = 9.4, 5.4 Hz,Rt-2.07 ((R)-1- 1H), 3.66 (m, 1H), 1.76 (d, J = 7.1 Hz, 3H),hydroxyethyl)oxazolidin-2- 1.04 (d, J = 6.4 Hz, 3H) one 228:(R)-3-(2-(((S)-1-(1-(4- 7.84 (br s, 1H), 7.76 (s, 1H), 7.57 (d, J = HRMSm/z chlorophenyl)-1H-pyrazol- 8.9 Hz, 2H), 7.44 (d, J = 9.0 Hz, 2H),7.13 447.1347 4-yl)ethyl)amino)-6- (s, 1H), 5.05 (m, 1H), 4.72 (m, 1H),4.47 (M + H)⁺; fluoropyrimidin-4-yl)-4- (m, 1H), 4.43-4.35 (m, 1H), 1.62(d, J = Rt-2.23 ((R)-1- 6.9 Hz, 3H), 0.96 (br m, 3H)hydroxyethyl)oxazolidin-2- one 229: (R)-3-(6-chloro-2- 7.82-7.69 (m,2H), 7.62 (s, 1H), 7.17 (t, J = HRMS m/z (((S)-1-(5-(4- 8.6 Hz, 2H),6.51 (s, 1H), 5.23 (d, J = 5.8 448.1192 fluorophenyl)isoxazol-3- Hz,1H), 4.89 (m, 1H), 4.59 (m, 1H), 4.47- (M + H)⁺;yl)ethyl)amino)pyrimidin-4- 4.40 (m, 1H), 3.91 (m, 1H), 1.68 (d, J = 7.1Rt-2.23 yl)-4-((R)-1- Hz, 3H), 1.07 (d, J = 6.3 Hz, 3H)hydroxyethyl)oxazolidin-2- one 230: (R)-3-(6-chloro-2- 7.59 (s, 1H),6.57 (s, 1H), 5.23 (m, 1H), HRMS m/z (((S)-1-(5- 4.82 (m, 1H), 4.56 (m,1H), 4.43-4.34 (m, 453.1662 (morpholinomethyl)isoxazol- 2H), 4.20 (m,1H), 3.97 (m, 4H), 3.24 (m, (M + H)⁺; 3-yl)ethyl)amino)pyrimidin-4- 4H),1.61 (d, J = 7.2 Hz, 3H), 1.04 (br s, Rt-1.26 yl)-4-((R)-1- 3H)hydroxyethyl)oxazolidin-2- one 231: (R)-3-(6-chloro-2- 7.55 (s, 1H),6.55 (s, 1H), 5.87 (m, 1H), HRMS m/z (((R)-1-(5- 5.05 (m, 1H), 4.65 (m,1H), 4.56 (m, 1H), 453.1651 (morpholinomethyl)isoxazol- 4.34-4.31 (m,2H), 4.20 (m, 1H), 3.97- (M + H)⁺; 3-yl)ethyl)amino)pyrimidin-4- 3.95(m, 4H), 3.18 (m, 4H), 1.62 (d, J = 7.0 Rt-1.27 yl)-4-((R)-1- Hz, 3H),1.18 (d, J = 6.5 Hz, 3H) hydroxyethyl)oxazolidin-2- one 232:(R)-3-(2-(((S)-1-(1-(4- 10.78 (d, J = 5.8 Hz, 1H), 7.98 (s, 1H), HRMSm/z chlorophenyl)-1H-pyrazol- 7.73 (s, 1H), 7.59 (d, J = 8.7 Hz, 2H),7.56 443.1596 4-yl)ethyl)amino)-6- (s, 1H), 7.43 (d, J = 8.7 Hz, 2H),5.00 (m, (M + H)⁺; methylpyrimidin-4-yl)-4- 1H), 4.89-4.74 (m, 1H), 4.60(dd, J = 9.6, Rt-1.62 ((R)-1- 2.2 Hz, 1H), 4.52-4.35 (m, 1H), 3.69 (dd,hydroxyethyl)oxazolidin-2- J = 6.5, 4.6 Hz, 1H), 2.52 (s, 3H), 1.69 (d,one J = 7.0 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H) 233: (R)-3-(6-chloro-2-8.63 (m, 1H), 8.14 (s, 1H), 7.95-7.89 (m, HRMS m/z(((S)-1-(2-(pyridin-2- 2H), 7.61 (s, 1H), 7.42 (m, 1H), 5.28 (m,447.1011 yl)thiazol-5- 1H), 4.52 (m, 1H), 4.47-4.35 (m, 3H), (M + H)⁺;yl)ethyl)amino)pyrimidin-4- 1.77 (m, 3H), 0.96 (br s, 3H) Rt-1.99yl)-4-((R)-1- hydroxyethyl)oxazolidin-2- one 234: (R)-3-(6-chloro-2-9.30 (m, 1H), 8.70 (m, 1H), 8.54 (m, 1H), HRMS m/z(((S)-1-(2-(pyridin-3- 7.88 (s, 1H), 7.69 (m, 1H), 7.61 (s, 1H),447.1011 yl)thiazol-5- 5.30 (m, 1H), 4.52 (m, 1H), 4.42-4.36 (m, (M +H)⁺; yl)ethyl)amino)pyrimidin-4- 3H), 1.76 (d, J = 6.9 Hz, 3H), 1.03 (brs, Rt-1.72 yl)-4-((R)-1- 3H) hydroxyethyl)oxazolidin-2- one 235:(R)-3-(6-chloro-2- 8.83 (m, 2H), 8.12 (m, 2H), 7.98 (s, 1H), HRMS m/z(((S)-1-(2-(pyridin-4- 7.63 (s, 1H), 5.40 (m, 1H), 4.73 (m, 1H),447.1006 yl)thiazol-5- 4.52 (m, 1H), 4.39 (m, 1H), 1.77 (m, 3H), (M +H)⁺; yl)ethyl)amino)pyrimidin-4- 1.00 (br s, 3H) Rt-1.52 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2- one 236: (R)-3-(2-(((S)-1-(5-(4- 11.03 (d, J= 6.8 Hz, 1H), 7.71 (d, J = 8.7 HRMS m/z chlorophenyl)isoxazol-3- Hz,2H), 7.56 (s, 1H), 7.46 (d, J = 8.7 Hz, 444.1443 yl)ethyl)amino)-6- 2H),6.70 (s, 1H), 5.32 (quin, J = 7.1 Hz, (M + H)⁺; methylpyrimidin-4-yl)-4-1H), 4.95 (ddd, J = 7.9, 4.4, 1.9 Hz, 1H), Rt-1.81 ((R)-1- 4.62 (dd, J =9.5, 1.9 Hz, 1H), 4.53-4.43 hydroxyethyl)oxazolidin-2- (m, 1H),4.06-3.94 (m, 1H), 2.51 (s, 3H), one 1.74 (d, J = 7.2 Hz, 3H), 1.13 (d,J = 6.6 Hz, 3H) 237: (R)-3-(2-(((S)-1-(2-(4- 11.12 (d, J = 5.4 Hz, 1H),7.88 (s, 1H), HRMS m/z chlorophenyl)thiazol-5- 7.81 (d, J = 8.7 Hz, 2H),7.62 (s, 1H), 7.45 460.1213 yl)ethyl)amino)-6- (d, J = 8.7 Hz, 2H),5.37-5.27 (m, 1H), (M + H)⁺; methylpyrimidin-4-yl)-4- 4.84 (ddd, J =8.2, 4.2, 2.2 Hz, 1H), 4.65 Rt-1.88 ((R)-1- (dd, J = 9.6, 2.2 Hz, 1H),4.44 (dd, J = 9.4, hydroxyethyl)oxazolidin-2- 8.3 Hz, 1H), 3.61-3.52 (m,1H), 2.52 (s, one 3H), 1.81 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 6.5 Hz,3H) 238: (R)-3-(2-(((S)-1-(1-(4- 11.13 (d, J = 8.3 Hz, 1H), 8.43 (s,1H), HRMS m/z chlorophenyl)-1H- 7.91 (s, 1H), 7.67 (s, 1H), 7.60 (d, J =8.8 443.1599 imidazol-4-yl)ethyl)amino)- Hz, 2H), 7.46 (d, J = 8.8 Hz,2H), 5.97 (M + H)⁺; 6-methylpyrimidin-4-yl)-4- (quin, J = 7.0 Hz, 1H),4.98 (ddd, J = 8.1, Rt-1.35 ((R)-1- 4.4, 2.4 Hz, 1H), 4.77 (dd, J = 9.6,2.3 Hz, hydroxyethyl)oxazolidin-2- 1H), 4.53-4.46 (m, 1H), 4.44-4.36 (m,one 1H), 2.55 (s, 3H), 1.70 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 6.6 Hz,3H) 239: (R)-3-(2-(((S)-1-(3-(4- 11.42 (d, J = 5.0 Hz, 1H), 8.00 (d, J =8.6 HRMS m/z chlorophenyl)-1,2,4- Hz, 2H), 7.64 (s, 1H), 7.48 (d, J =8.6 Hz, 445.1393 oxadiazol-5- 2H), 5.30-5.20 (m, 1H), 4.77 (ddd, J =(M + H)⁺; yl)ethyl)amino)-6- 7.9, 4.5, 2.0 Hz, 1H), 4.57 (dd, J = 9.5,1.9 Rt-1.96 methylpyrimidin-4-yl)-4- Hz, 1H), 4.40 (dd, J = 9.4, 8.2 Hz,1H), ((R)-1- 3.65-3.55 (m, 1H), 2.56 (s, 3H), 1.90 (d, J =hydroxyethyl)oxazolidin-2- 7.2 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H) one240: (R)-3-(2-(((S)-1-(1-(4- 10.80 (d, J = 7.3 Hz, 1H), 7.79 (d, J = 2.5HRMS m/z chlorophenyl)-1H-pyrazol- Hz, 1H), 7.54-7.48 (m, 3H), 7.46-7.41443.1601 3-yl)ethyl)amino)-6- (m, 2H), 6.58 (d, J = 2.5 Hz, 1H), 5.40-(M + H)⁺; methylpyrimidin-4-yl)-4- 5.30 (m, 1H), 4.85 (ddd, J = 7.7,5.1, 2.3 Rt-1.66 ((R)-1- Hz, 1H), 4.50-4.38 (m, 2H), 4.02-3.93hydroxyethyl)oxazolidin-2- (m, 1H), 2.50 (s, 3H), 1.71 (d, J = 7.1 Hz,one 3H), 0.94 (d, J = 6.5 Hz, 3H) 241: (R)-3-(2-(((S)-1-(1-(4- 11.00 (m,1H), 8.15 (s, 1H), 7.69 (d, J = HRMS m/z chlorophenyl)-1H-1,2,3- 8.5 Hz,2H), 7.53 (s, 1H), 7.51 (d, J = 8.5 444.1548triazol-4-yl)ethyl)amino)-6- Hz, 2H), 5.51 (m, 1H), 4.70 (m, 1H), 4.58(M + H)⁺; methylpyrimidin-4-yl)-4- (m, 1H), 4.51 (m, 1H), 3.96 (m, 1H),2.50 Rt-1.54 ((R)-1- (s, 3H), 1.78 (d, J = 6.5 Hz, 3H), 1.17 (d, J =hydroxyethyl)oxazolidin-2- 6.5 Hz, 3H) one 242: (R)-3-(6-chloro-2- 7.97(s, 1H), 7.69 (m, 2H), 7.60 (s, 1H), HRMS m/z (((S)-1-(1-(4- 7.52 (d, J= 8.9 Hz, 2H), 5.41 (m, 1H), 4.97 464.1003 chlorophenyl)-1H-1,2,3- (m,1H), 4.54 (m, 1H), 4.43 (m, 1H), 3.77 (M + H)⁺; triazol-4- (m, 1H), 1.71(d, J = 7.0 Hz, 3H), 1.05 (br Rt-2.15 yl)ethyl)amino)pyrimidin-4- s, 3H)yl)-4-((R)-1- hydroxyethyl)oxazolidin-2- one 243:(R)-3-(2-(((S)-1-(1-(4- 10.91 (d, J = 7.3 Hz, 1H), 8.15 (s, 1H), HRMSm/z chlorophenyl)-1H-1,2,3- 7.89 (d, J = 7.0 Hz, 1H), 7.75 (d, J = 7.0430.1398 triazol-4- Hz, 1H), 7.70 (d, J = 8.5 Hz, 2H), 7.52 (d, (M +H)⁺; yl)ethyl)amino)pyrimidin-4- J = 8.5 Hz, 2H), 5.53 (quin, J = 6.9Hz, 1H), Rt-1.56 yl)-4-((R)-1- 5.04 (m, 1H), 4.60-4.50 (m, 2H), 3.99 (m,hydroxyethyl)oxazolidin-2- 1H), 1.79 (d, J = 7.2 Hz, 3H), 1.19 (d, J =one 6.5 Hz, 3H) 244: (R)-3-(2-(((S)-1-(4- 11.05 (d, J = 5.9 Hz, 1H),7.56 (s, 1H), HRMS m/z (1,1-difluoroethyl)-2- 7.52 (t, J = 7.8 Hz, 1H),7.31 (d, J = 8.7 Hz, 425.1803 fluorophenyl)ethyl)amino)- 1H), 7.24 (s,1H), 5.37 (quin, J = 6.7 Hz, (M + H)⁺; 6-methylpyrimidin-4-yl)-4- 1H),4.75 (m, 1H), 4.56 (dd, J = 9.6, 2.3 Rt-1.68 ((R)-1- Hz, 1H), 4.40 (m,1H), 3.47 (m, 1H), 2.53 hydroxyethyl)oxazolidin-2- (s, 3H), 1.92 (t, J =18.2, Hz, 3H), 1.66 (d, one J = 7.0 Hz, 3H), 0.84 (d, J = 6.5 Hz, 3H)245: (R)-3-(2-(((S)-1-(2,5- 11.1 (d, J = 6.6 Hz, 1H), 7.58 (s, 1H), 7.25HRMS m/z difluoro-4-(2,2,2- (m, 1H), 6.83 (dd, J = 10.5, 6.6 Hz, 1H),477.1574 trifluoroethoxy)phenyl)eth- 5.33 (quin, J = 6.9 Hz, 1H), 4.83(ddd, J = (M + H)⁺; yl)amino)-6- 8.1, 4.7, 2.3 Hz, 1H), 4.59 (dd, J =9.6, 2.3 Rt-1.78 methylpyrimidin-4-yl)-4- Hz, 1H), 4.48-4.37 (m, 3H),3.83 (m, 1H), ((R)-1- 2.53 (s, 3H), 1.61 (d, J = 7.0 Hz, 3H), 0.96hydroxyethyl)oxazolidin-2- (d, J = 6.5 Hz, 3H) one 246: (R)-4-((R)-1-11.16 (d, J = 6.9 Hz, 1H), 9.54 (d, J = 1.9 HRMS m/zhydroxyethyl)-3-(6-methyl- Hz, 1H), 8.76 (dd, J = 8.3, 2.1 Hz, 1H),441.1710 2-(((S)-1-(2-(6- 8.00 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.63(M + H)⁺; methylpyridin-3-yl)thiazol- (s, 1H), 5.43 (quin, J = 6.9 Hz,1H), 5.06 Rt-1.16 5-yl)ethyl)amino)pyrimidin- (ddd, J = 7.9, 4.2, 1.8Hz, 1H), 4.74 (dd, 4-yl)oxazolidin-2-one J = 9.6, 1.9 Hz, 1H), 4.14 (m,1H), 2.86 (s, 3H), 2.52 (s, 3H), 1.87 (d, J = 7.1 Hz, 3H), 1.13 (d, J =6.4 Hz, 3H) 247: (R)-4-((R)-1- 11.05 (br s, 1H), 9.21 (s, 1H), 8.34 (d,J = HRMS m/z hydroxyethyl)-3-(2-(((S)-1- 8.8 Hz, 1H), 7.97 (d, J = 7.0Hz, 1H), 7.92 481.1272 (2-(6- (s, 1H), 7.82 (d, J = 7.0 Hz, 1H), 7.79(d, (M + H)⁺; (trifluoromethyl)pyridin-3- J = 8.3 Hz, 1H), 5.35 (m, 1H),4.85 (m, 1H), Rt-1.77 yl)thiazol-5- 4.64 (m, 1H), 4.46 (m, 1H), 3.58 (m,1H), yl)ethyl)amino)pyrimidin-4- 1.85 (d, J = 6.9 Hz, 3H), 0.96 (d, J =6.4 yl)oxazolidin-2-one Hz, 3H) 248: (R)-4-((R)-1- 11.05 (br s, 1H),8.84 (d, J = 5.1 Hz, 1H), HRMS m/z hydroxyethyl)-3-(2-(((S)-1- 8.15 (s,1H), 7.99 (d, J = 7.1 Hz, 1H), 7.95 481.1268 (2-(2- (s, 1H), 7.92 (dd, J= 5.1, 1.3 Hz, 1H), 7.83 (M + H)⁺; (trifluoromethyl)pyridin-4- (d, J =7.0 Hz, 1H), 5.36 (m, 1H), 4.85 (m, Rt-1.72 yl)thiazol-5- 1H), 4.65 (dd,J = 9.7, 2.0 Hz, 1H), 4.46 yl)ethyl)amino)pyrimidin-4- (m, 1H), 3.62 (m,1H), 1.85 (d, J = 6.9 Hz, yl)oxazolidin-2-one 3H), 0.97 (d, J = 6.5 Hz,3H) 249: methyl 2-(((S)-1-(2- 8.27 (s, 1H), 7.96 (s, 1H), 7.80 (d, J =8.6 HRMS m/z (4-chlorophenyl)thiazol-5- Hz, 2H), 7.47 (d, J = 8.6 Hz,2H), 5.41 (m, 504.1111 yl)ethyl)amino)-6-((R)-4- 1H), 4.66 (m, 1H), 4.45(m, 1H), 4.01 (s, (M + H)⁺; ((R)-1-hydroxyethyl)-2- 3H), 3.75 (m, 1H),1.78 (d, J = 6.9 Hz, 3H), Rt-2.17 oxooxazolidin-3- 0.98 (d, J = 6.1 Hz,3H) yl)pyrimidine-4- carboxylate 250: (R)-3-(2-(((S)-1-(1-(4- 11.00 (d,J = 8.5 Hz, 1H), 7.95 (m, 1H), LCMS m/z chlorophenyl)-2-methyl- 7.87 (m,1H), 7.61 (m, 2H), 7.43 (d, J = 1.8 443.2 (M + H)⁺; 1H-imidazol-4- Hz,1H), 7.35 (m, 2H), 5.95 (m, 1H), 5.02 Rt-0.60yl)ethyl)amino)pyrimidin-4- (m, 1H), 4.80 (dd, J = 9.6, 2.4 Hz, 1H),yl)-4-((R)-1- 4.50 (m, 1H), 4.40 (m, 1H), 2.60 (m, 3H),hydroxyethyl)oxazolidin-2- 1.70 (m, 3H), 1.07 (m, 3H) one 251:(R)-3-(2-(((S)-1-(2-(4- 10.92 (br s, 1H), 7.95 (m, 3H), 7.84 (s, 1H),LCMS m/z (difluoromethyl)phenyl)thiazol- 7.80 (d, J = 7.0 Hz, 1H), 7.60(d, J = 8.2 462.2 (M + H)⁺; 5-yl)ethyl)amino)pyrimidin-4- Hz, 2H), 6.69(t, J = 56 Hz, 1H), 5.27 (m, Rt-0.70 yl)-4-((R)-1-hydroxy- 1H), 4.81(ddd, J = 8.2, 4.3, 2.1 Hz, 1H), ethyl)oxazolidin-2-one 4.64 (dd, J =9.6, 2.1 Hz, 1H), 4.45 (m, 1H), 3.39 (br m, 1H), 1.84 (d, J = 7.0 Hz,3H), 0.89 (d, J = 6.5 Hz, 3H) 252: (R)-3-(2-((S)-1-(2- (CD₃OD) 0.77 (br.s., 3 H) 1.64 (d, J = 6.99 HRMS (B) m/z fluoro-4-(trifluoro- Hz, 3 H)4.40-4.47 (m, 1 H) 4.57 (dd, 415.1402 methyl)phenyl)ethylamino) J =9.22, 2.52 Hz, 1 H) 5.43-5.51 (m, 1 H) (M + H)⁺;pyrimidin-4-yl)-4-((R)-1- 7.50 (d, J = 9.15 Hz, 2 H) 7.62 (t, J = 7.73Hz, Rt-2.18 min hydroxyethyl)oxazolidin-2- 1 H) 7.67 (d, J = 6.85 Hz, 1H) 8.15 (d, one J = 6.80 Hz, 1 H) 253: (R)-3-(2-((S)-1-(4-(1- (CD₃OD)0.80 (br. s., 3 H) 0.95-1.00 (m, 2 HRMS (B) m/z ethoxycyclopropyl)-2- H)1.15 (t, J = 7.07 Hz, 3 H) 1.19-1.23 (m, 431.2090 fluorophenyl) 2 H)1.61 (d, J = 6.99 Hz, 3 H) 3.44 (qd, (M + H)⁺;ethylamino)pyrimidin-4-yl)- J = 7.05, 1.34 Hz, 2 H) 4.41-4.49 (m, 1 H)Rt-1.72 min 4-((R)-1-hydroxyethyl) 4.59 (dd, J = 9.19, 2.49 Hz, 1 H)5.40 (br. s., oxazolidin-2-one 1 H) 7.06 (d, J = 2.15 Hz, 1 H) 7.09 (s,1 H) 7.36 (t, J = 7.92 Hz, 1 H) 7.66 (d, J = 6.85 Hz, 1 H) 8.12 (d, J =7.14 Hz, 1 H) 254: 2-chloro-N- (CD₃OD) 0.86 (br. s., 3 H) 1.57 (d, J =6.99 HRMS (B) m/z cyclopentyl-4-((S)-1-(4- Hz, 3 H) 1.59-1.69 (m, 3 H)1.74 (d, 474.1908 ((R)-4-((R)-1- J = 4.99 Hz, 2 H) 1.95-2.06 (m, 2 H)2.66 (M + H)⁺; hydroxyethyl)-2- (s, 1 H) 4.29 (d, J = 6.46 Hz, 1 H)4.38- Rt-1.58 min oxooxazolidin-3- 4.46 (m, 1 H) 4.57 (dd, J = 9.24,2.54 Hz, 1 yl)pyrimidin-2- H) 5.13 (br. s., 1 H) 7.39 (s, 2 H) 7.47 (s,1 ylamino)ethyl)benzamide H) 7.61 (d, J = 6.21 Hz, 1 H) 8.13 (br. s., 1H) 8.40 (br. s., 1 H) 255: 1-(3-fluoro-4-((S)-1- (CD₃OD) 0.80 (br. s., 3H) 1.47-1.51 (m, 2 HRMS (B) m/z (4-((R)-4-((R)-1- H) 1.60 (d, J = 6.94Hz, 3 H) 1.72-1.76 (m, 412.1785 hydroxyethyl)-2- 2 H) 4.41-4.47 (m, 1 H)4.58 (dd, J = 9.22, (M + H)⁺; oxooxazolidin-3- 2.57 Hz, 1 H) 5.39 (br.s., 1 H) 7.12 (dd, Rt-1.51 min yl)pyrimidin-2- J = 11.64, 1.91 Hz, 1 H)7.18 (dd, J = 8.09, ylamino)ethyl)phenyl)cyclo- 1.79 Hz, 1 H) 7.41 (t, J= 8.05 Hz, 1 H) 7.64 propanecarbonitrile (d, J = 6.65 Hz, 1 H) 8.13 (d,J = 6.80 Hz, 1 H) 256: (R)-3-(2-((S)-1-(2- (CD₃OD) 0.82 (br. s., 3 H)1.64 (d, J = 6.94 HRMS (B) m/z fluoro-4-(1-methyl-1H- Hz, 3 H) 3.92 (s,3 H) 4.07 (d, J = 16.09 Hz, 427.1890 pyrazol-4-yl)phenyl) 1 H) 4.43-4.50(m, 1 H) 4.60 (dd, J = 9.22, (M + H)⁺; ethylamino)pyrimidin-4-yl)- 2.47Hz, 1 H) 4.91 (ddd, J = 8.20, 3.97, 2.45 Rt-1.37 min4-((R)-1-hydroxyethyl) Hz, 2 H) 5.45 (br. s., 1 H) 7.31-7.44 (m, 3oxazolidin-2-one H) 7.73 (d, J = 7.09 Hz, 1 H) 7.82 (d, J = 0.68 Hz, 1H) 7.98 (s, 1 H) 8.13 (d, J = 7.04 Hz, 1 H) 257: (R)-4-((R)-1- (CD₃OD)0.80 (br. s., 3 H) 1.62 (d, J = 6.94 HRMS (B) m/zhydroxyethyl)-3-(2-((S)-1- Hz, 3 H) 3.92 (s, 3 H) 3.99 (br. s., 1 H)409.1982 (4-(1-methyl-1H-pyrazol-4- 4.42-4.50 (m, 1 H) 4.60 (dd, J =9.24, 2.45 (M + H)⁺; yl)phenyl)ethylamino) Hz, 1 H) 5.21 (br. s., 1 H)7.38 (d, J = 8.17 Rt-1.27 min pyrimidin-4-yl)oxazolidin- Hz, 2 H)7.53-7.59 (m, 2 H) 7.73 (d, 2-one J = 7.14 Hz, 1 H) 7.79 (d, J = 0.68Hz, 1 H) 7.93 (s, 1 H) 8.12 (d, J = 6.11 Hz, 1 H) 258:(R)-3-(2-((S)-1-(2- (CD₃OD) 0.83 (br. s., 3 H) 1.65 (d, J = 6.99 HRMS(B) m/z fluoro-4-(1H-pyrazol-4- Hz, 3 H) 4.07 (br. s., 1 H) 4.43-4.52(m, 1 413.1732 yl)phenyl)ethylamino) H) 4.61 (dd, J = 9.24, 2.45 Hz, 1H) 4.90- (M + H)⁺; pyrimidin-4-yl)-4-((R)-1- 4.94 (m, 2 H) 5.45 (br. s.,1 H) 7.36-7.42 Rt-1.26 min hydroxyethyl)oxazolidin-2- (m, 3 H) 7.73 (d,J = 7.04 Hz, 1 H) 7.98 (s, 2 one H) 8.13 (d, J = 6.90 Hz, 1 H) 259:(R)-3-(5-fluoro-2-((S)- (CD₃OD) 0.75 (br. s., 3 H) 1.54 (d, J = 7.04HRMS (B) m/z 1-(2-fluoro-4- Hz, 3 H) 3.85 (br. s., 1 H) 4.42-4.55 (m, 2433.1299 (trifluoromethyl)phenyl)eth- H) 5.27 (q, J = 6.99 Hz, 1 H) 7.42(M + H)⁺; ylamino)pyrimidin-4-yl)-4- (d, J = 8.90 Hz, 2 H) 7.58 (t, J =7.92 Hz, 1 H) Rt-2.03 min ((R)-1-hydroxyethyl) 8.21 (d, J = 2.74 Hz, 1H) oxazolidin-2-one 260: (R)-3-(2-((S)-1-(2- (CD₃OD) 0.73-0.87 (m, 7 H)1.39 (s, 3 H) HRMS (B) m/z fluoro-4-(1- 1.60 (d, J = 6.94 Hz, 3 H) 3.99(br. s., 1 H) 401.1992 methylcyclopropyl)phenyl) 4.40-4.49 (m, 1 H) 4.59(dd, J = 9.19, 2.54 (M + H)⁺; ethylamino)pyrimidin-4-yl)- Hz, 1 H) 5.39(br. s., 1 H) 7.01 (dd, Rt-1.87 min 4-((R)-1-hydroxyethyl) J = 12.40,1.74 Hz, 1 H) 7.05 (dd, J = 8.00, oxazolidin-2-one 1.79 Hz, 1 H) 7.29(t, J = 8.09 Hz, 1 H) 7.69 (d, J = 6.99 Hz, 1 H) 8.12 (d, J = 6.94 Hz, 1H) 261: (R)-3-(2-((S)-1-(2- (CD₃OD) 8.12 (d, J = 6.7 Hz, 1 H), 7.69 (d,HRMS (B) m/z fluoro-4- J = 7.0 Hz, 1 H), 7.31 (t, J = 8.0 Hz, 1 H),389.1987 isopropylphenyl)ethylami- 6.98-7.09 (m, 2 H), 5.42 (d, J = 12.9Hz, 1 (M + H)⁺; no)pyrimidin-4-yl)-4-((R)-1- H), 4.59 (dd, J = 9.2, 2.5Hz, 1 H), 4.40- Rt-1.83 min hydroxyethyloxazolidin-2- 4.49 (m, 1 H),2.91 (spt, J = 6.8 Hz, 1 H), one 1.61 (d, J = 6.7 Hz, 3 H), 1.23 (d, J =7.0 Hz, 6 H), 0.80 (br. s., 3 H) 262: (R)-3-(5-fluoro-2-((S)- (CD₃OD)0.75 (br. s., 3 H) 1.53 (d, J = 6.94 Hz, HRMS (B) m/z1-(2-fluoro-4-(1-methyl- 3 H) 3.91 (s, 3 H) 4.42-4.56 (m, 2 H) 445.18001H-pyrazol-4- 4.65 (br. s., 1 H) 5.22 (m, J = 7.04 Hz, 1 H) (M + H)⁺;yl)phenyl)ethylamino)pyrim- 7.22-7.31 (m, 2 H) 7.31-7.40 (m, 1 H)Rt-1.64 min idin-4-yl)-4-((R)-1- 7.79 (s, 1 H) 7.94 (s, 1 H) 8.21 (br.s., 1 H) hydroxyethyl)oxazolidin-2- one 263: (R)-3-(5-fluoro-2-((S)-(CD₃OD) 0.52-0.78 (m, 5 H) 0.82 (br. s., 2 HRMS (B) m/z1-(2-fluoro-4-(1- H) 1.36 (s, 3 H) 1.49 (d, J = 6.99 Hz, 3 H) 419.1895methylcyclopropyl)phenyl) 3.86 (br. s., 1 H) 4.42-4.56 (m, 2 H) 4.62(M + H)⁺; ethylamino)pyrimidin-4-yl)- (br. s., 1 H) 5.18 (m, J = 6.31Hz, 1 H) 6.90- Rt-2.21 min 4-((R)-1-hydroxyethyl) 7.00 (m, 2 H) 7.24 (t,J = 8.17 Hz, 1 H) 8.20 oxazolidin-2-one (d, J = 2.93 Hz, 1 H) 264:(R)-3-(5-fluoro-2-((S)- (CD₃OD) 0.76 (br. s., 3 H) 1.53 (d, J = 6.90HRMS (B) m/z 1-(2-fluoro-4-(1H-pyrazol- Hz, 3 H) 3.91 (br. s., 1 H)4.42-4.57 (m, 2 431.1640 4-yl)phenyl) H) 4.66 (br. s., 1 H) 5.23 (d, J =6.41 Hz, 1 (M + H)⁺; ethylamino)pyrimidin-4-yl)- H) 7.28-7.40 (m, 3 H)7.97 (s, 2 H) 8.21 Rt-1.55 min 4-((R)-1-hydroxyethyl) (br. s., 1 H)oxazolidin-2-one 265: (R)-3-(5-fluoro-2-((S)- (CD₃OD) 0.71 (br. s., 3 H)1.21 (d, J = 6.94 HRMS (B) m/z 1-(2-fluoro-4- Hz, 6 H) 1.50 (d, J = 6.99Hz, 3 H) 2.87 (dt, 407.1890 isopropylphenyl)ethylami- J = 13.72, 6.83Hz, 1 H) 3.89 (br. s., 1 H) (M + H)⁺; no)pyrimidin-4-yl)-4-((R)-1-4.43-4.56 (m, 2 H) 4.63 (br. s., 1 H) 5.20 Rt-2.18 min hydroxyethyl)oxazolidin- (q, J = 6.52 Hz, 1 H) 6.90-7.00 (m, 2 H) 2-one 7.26 (t, J =7.90 Hz, 1 H) 8.21 (d, J = 2.84 Hz, 1 H) 266: (R)-3-(5-fluoro-2-((S)-(CD₃OD) 0.73 (br. s., 3 H) 1.47-1.52 (m, HRMS (B) m/z 1-(2-fluoro-4-(2-9 H) 4.43-4.55 (m, 3 H) 4.59-4.67 (m, 1 H) 423.1838 hydroxypropan-2-5.15-5.27 (m, 1 H) 7.15-7.23 (m, 2 H) (M + H)⁺;yl)phenyl)ethylamino)pyrim- 7.30 (t, J = 8.09 Hz, 1 H) 8.20 (d, J =Rt-1.59 min idin-4-yl)-4-((R)-1- 3.08 Hz, 1 H)hydroxyethyl)oxazolidin-2- one 267: (R)-3-(2-(((S)-1-(2,5- (CD₃OD) 0.79(br. s., 3 H) 1.52 (d, J = 6.99 HRMS (B) m/z difluoro-4-(1-methyl-1H-Hz, 3 H) 3.92 (s, 3 H) 4.43-4.56 (m, 2 H) 463.1708 pyrazol-4- 4.64 (d, J= 3.42 Hz, 1 H) 5.21 (q, J = 6.83 (M + H)⁺; yl)phenyl)ethyl)amino)-5-Hz, 1 H) 7.14 (dd, J = 11.40, 6.31 Hz, 1 H) Rt-1.72 minfluoropyrimidin-4-yl)-4- 7.39 (dd, J = 10.93, 6.14 Hz, 1 H) 7.86 (d,((R)-1-hydroxyethyl) J = 0.59 Hz, 1 H) 8.00 (d, J = 1.86 Hz, 1 H)oxazolidin-2-one 8.23 (d, J = 3.03 Hz, 1 H) 268: (R)-3-(2-(((S)-1-(2-(4-(CD₃CN) 0.98 (d, J = 6.65 Hz, 3 H) 1.72 (d, HRMS (B) m/z chlorophenyl)thiazol-5- J = 7.04 Hz, 3 H) 4.00 (br. s., 1 H) 4.26- 446.1060yl)ethyl)amino) pyrimidin- 4.42 (m, 1 H) 4.51 (dd, J = 8.80, 2.93 Hz, 1(M + H)⁺; 4-yl)-4-((S)-1- H) 4.62 (dd, J = 7.24, 1.37 Hz, 1 H) 5.49Rt-1.81 min hydroxyethyl)oxazolidin-2- (quin, J = 6.85 Hz, 1 H) 7.49 (d,J = 8.61 Hz, one 2 H) 7.66-7.78 (m, 2 H) 7.91 (d, J = 8.61 Hz, 2 H) 8.05(d, J = 7.04 Hz, 1 H) 10.52 (br. s., 1 H) 269: (R)-3-(6-chloro-2-(CDCl₃) 0.80 (br. s., 3 H) 1.26 (s, 3 H) 1.63- HRMS (B) m/z(((S)-1-(2-fluoro-4-(2- 1.73 (m, 9 H) 4.28-4.36 (m, 1 H) 4.44 441.1501fluoropropan-2- (dd, J = 9.39, 2.54 Hz, 1 H) 4.64 (br. s., 1 H) (M +H)⁺; yl)phenyl)ethyl)amino)pyrim- 5.21 (br. s., 1 H) 7.07-7.18 (m, 2 H)7.28- Rt-2.35 min idin-4-yl)-4-((R)-1- 7.33 (m, 1 H) 7.51 (s, 1 H)hydroxyethyl)oxazolidin-2- one 270: (R)-3-(5-chloro-2- (CD₃OD) δ HRMS(B) m/z (((S)-1-(1-(4- 8.20 (s, 1 H), 8.03 (d, J = 1.2 Hz, 1 H), 7.30-399.1029 chlorophenyl)-1H- 7.52 (m, 6 H), 5.06 (d, J = 6.7 Hz, 1 H),(M + H)⁺ imidazol-4- 4.67 (dt, J = 8.6, 6.1 Hz, 1 H), 4.45 (t, J = 8.8RT = 1.95 min. yl)ethyl)amino)pyrimidin-4- Hz, 1 H), 4.31 (dd, J = 9.0,6.3 Hz, 1 H), yl)-4-((R)-1- 3.81 (br. s., 1 H), 1.49 (d, J = 6.7 Hz, 3H), hydroxyethyl)oxazolidin-2- 0.91 (br. s., 3 H) one 271:(R)-3-(2-((S)-1-(2,5- (CD₃OD) 8.14 (br. s., 1 H), 7.64 (d, J = 6.7 HRMS(B) m/z difluoro-4- Hz, 1 H), 7.07 (dd, J = 10.2, 6.3 Hz, 2 H),407.1895, isopropylphenyl)ethylami- 5.37 (d, J = 5.1 Hz, 1 H), 4.85 (s,1H), 4.57 (M + H)⁺, no)pyrimidin-4-yl)-4-((R)-1- (dd, J = 9.4, 2.3 Hz, 1H), 4.38-4.49 (m, 1 RT = 1.95 min. hydroxyethyl)oxazolidin-2- H), 3.96(br. s., 1 H), 3.11-3.25 (m, 1 H), one 1.57 (d, J = 7.0 Hz, 3 H), 1.23(dd, J = 7.0, 2.0 Hz, 6 H), 0.80 (br. s., 3 H) 272: (R)-3-(2-(((S)-1-(4-(CD₃OD) 8.14 (d, J = 5.9 Hz, 1 H), 7.51 (d, HRMS (B) m/z bromo-2,5- J =6.3 Hz, 1 H), 7.44 (dd, J = 9.4, 5.5 Hz, 1 443.0527,difluorophenyl)ethyl)ami- H), 7.24 (dd, J = 9.0, 6.3 Hz, 1 H), 5.33 (q,(M + H)⁺, no)pyrimidin-4-yl)-4-((R)-1- J = 6.7 Hz, 1 H), 4.85 (s, 8 H),4.54 (dd, RT = 1.74 min. hydroxyethyl)oxazolidin-2- J = 9.2, 2.5 Hz, 2H), 4.34-4.47 (m, 1 H), one 1.54 (d, J = 6.7 Hz, 3 H), 0.83 (br. s., 3H) 273: (R)-3-(2-((S)-1-(5- (CD₃OD) 8.55 (d, J = 1.2 Hz, 1 H), 8.16 (d,HRMS (B) m/z chloro-6-(1,1- J = 5.9 Hz, 1 H), 7.99 (s, 1 H), 7.64 (d,428.1299, difluoroethyl)pyridin-3- J = 5.9 Hz, 1 H), 5.27 (br. s., 1 H),4.85(s, 2 (M + H)⁺, yl)ethylamino)pyrimidin-4- H), 4.56 (dd, J = 9.0,2.3 Hz, 1 H), 4.39- RT = 1.65 min. yl)-4-((R)-1- 4.47 (m, 1 H), 2.04 (t,J = 19.0 Hz, 3 H), 1.63 hydroxyethyl)oxazolidin-2- (d, J = 7.0 Hz, 3 H),0.82 (br. s., 3 H) one 274: (R)-3-(2-((S)-1-(5- (CD₃OD) 8.15 (d, J = 2.0Hz, 2 H), 7.92 (d, HRMS (B) m/z chloro-6-(2,2,2- J = 2.3 Hz, 1 H), 7.71(d, J = 7.0 Hz, 1 H), 462.1149, trifluoroethoxy)pyridin-3- 5.25 (br. s.,1 H), 4.89-4.99 (m, 3H), 4.59 (M + H)⁺, yl)ethylamino)pyrimidin-4- (dd,J = 9.4, 2.3 Hz, 1 H), 4.41-4.50 (m, 1 RT = 1.87 min. yl)-4-((R)-1- H),4.00 (br. s., 1 H), 1.62 (d, J = 7.0 Hz, 6 hydroxyethyl)oxazolidin-2- H)one 275: (R)-3-(2-((S)-1-(4- (CD₃OD) 8.16 (br. s., 1 H), 7.71 (d, J =6.7 HRMS (B) m/z bromo-2,3- Hz, 1 H), 7.36-7.48 (m, 1 H), 7.09-7.22443.0532, difluorophenyl)ethylamino) (m, 1 H), 5.42 (br. s., 1 H), 4.87(s, 1 H), (M + H)⁺, pyrimidin-4-yl)-4-((R)-1- 4.57 (dd, J = 9.0, 2.3 Hz,1 H), 4.39-4.50 RT = 1.81 min. hydroxyethyl)oxazolidin-2- (m, 1 H), 3.82(br. s., 1 H), 1.62 (d, J = 7.0 one Hz, 6 H) 276: (R)-3-(2-(((S)-1-(4-(CD₃OD) 8.22 (d, J = 2.3 Hz, 1 H), 7.41 (dd, HRMS (B) m/z bromo-2,5- J =9.0, 5.5 Hz, 1 H), 7.21 (dd, J = 9.2, 6.5 461.0432,difluorophenyl)ethyl)ami- Hz, 1 H), 5.13-5.23 (m, 1 H), (M + H)⁺,no)-5-fluoropyrimidin-4-yl)- 4.86 (s, 1 H), 4.38-4.55 (m, 2 H), 3.99- RT= 2.01 min. 4-((R)-1- 4.16 (m, 1 H), 1.49 (d, J = 7.0 Hz, 6 H)hydroxyethyl)oxazolidin-2- one 277: (R)-3-(2-(((S)-1-(4- (CD₃OD) 8.20(d, J = 2.3 Hz, 1 H), 7.18- HRMS (B) m/z bromo-2- 7.38 (m, 3 H), 5.18(q, J = 7.0 Hz, 1 H), 4.61 443.0534, fluorophenyl)ethyl)amino)- (t, J =9.0 Hz, 1 H), 4.42-4.55 (m, 2 H), 3.89 (M + H)⁺,5-fluoropyrimidin-4-yl)-4- (br. s., 1 H), 1.49 (d, J = 7.0 Hz, 6 H) RT =1.99 min. ((R)-1- hydroxyethyl)oxazolidin-2- one 278:(R)-3-(2-(((S)-1-(4- (CD₃OD) 8.21 (d, J = 2.7 Hz, 1 H), 7.36 (t, HRMS(B) m/z chloro-2- J = 8.4 Hz, 1 H), 7.05-7.21 (m, 2 H), 5.20 399.1029,fluorophenyl)ethyl)amino)- (q, J = 7.0 Hz, 1 H), 4.62 (d, J = 8.6 Hz, 1H), (M + H)⁺, 5-fluoropyrimidin-4-yl)-4- 4.42-4.56 (m, 2 H), 3.90 (br.s., 1 H), 1.50 RT = 1.95 min. ((R)-1- (d, J = 7.0 Hz, 6 H)hydroxyethyl)oxazolidin-2- one 279: (R)-3-(2-((S)-1-(5- (CD₃OD) 8.45 (s,1 H), 8.21 (d, J = 2.7 Hz, HRMS (B) m/z bromo-3-fluoropyridin-2- 1 H),7.86 (dd, J = 9.4, 2.0 Hz, 1 H), 5.35 (q, 444.0483, yl)ethylamino)-5- J= 6.7 Hz, 1 H), 4.67-4.77 (m, 1H), 4.43- (M + H)⁺,fluoropyrimidin-4-yl)-4- 4.58 (m, 2 H), 4.08-4.20 (m, 1 H), 1.51 (d, RT= 1.75 min. ((R)-1- J = 6.7 Hz, 3 H), 1.09 (d, J = 6.7 Hz, 3 H)hydroxyethyl)oxazolidin-2- one 280: (R)-3-(2-((R)-1-(5- (CD₃OD) 8.44 (s,1 H), 8.22 (d, J = 2.7 Hz, HRMS (B) m/z bromo-3-fluoropyridin-2- 1 H),7.86 (dd, J = 9.4, 1.6 Hz, 1 H), 5.30- 444.0478, yl)ethylamino)-5- 5.38(m, 1 H), 4.61-4.71 (m, 1H), 4.50- (M + H)⁺, fluoropyrimidin-4-yl)-4-4.58 (m, 1 H), 4.43-4.49 (m, 1 H), 3.92 RT = 1.75 min. ((R)-1- (br. s.,1 H), 1.52 (d, J = 7.0 Hz, 6 H) hydroxyethyl)oxazolidin-2- one 281:(R)-3-(2-((S)-1-(3-(4- (CD₃OD) 8.27 (br. s., 1 H), 8.01 (dd, HRMS (B)m/z chlorophenyl)-1,2,4- J = 8.6, 2.3 Hz, 2 H), 7.47-7.56 (m, 2 H),449.1140, oxadiazol-5- 5.30-5.43 (m, 1 H), 4.68 (d, J = 13.7 Hz, 1 (M +H)⁺, yl)ethylamino)-5- H), 4.40-4.57 (m, 2 H), 4.00 (br. s., 1 H), RT =2.04 min. fluoropyrimidin-4-yl)-4- 1.72 (d, J = 7.0 Hz, 6 H) ((R)-1-hydroxyethyl)oxazolidin-2- one 282: (R)-3-(2-((S)-1-(5- (CD₃OD) 8.65 (d,J = 2.0 Hz, 1 H), 8.22 (d, HRMS (B) m/z bromopyridin-2- J = 2.3 Hz, 1H), 8.07 (dd, J = 8.6, 2.3 Hz, 1 426.0574, yl)ethylamino)-5- H), 7.51(d, J = 8.2 Hz, 1 H), 5.00-5.08 (m, (M + H)⁺, fluoropyrimidin-4-yl)-4- 1H), 4.61 (br. s., 1 H), 4.42-4.55 (m, 2 RT = 1.61 min. ((R)-1- H),4.06-4.17 (m, 1 H), 1.55 (d, J = 7.0 Hz, hydroxyethyl)oxazolidin-2- 3H),1.08 (d, J = 6.7 Hz, 3 H) one 283: (R)-3-(2-(((S)-1-(4- (CD₃OD) 8.21 (d,J = 2.7 Hz, 1 H), 7.52 (t, HRMS (B) m/z bromo-3- J = 7.6 Hz, 1 H), 7.21(dd, J = 9.8, 2.0 Hz, 1 443.0526, fluorophenyl)ethyl)amino)- H), 7.12(dd, J = 8.2, 2.0 Hz, 1 H), 4.88- (M + H)⁺, 5-fluoropyrimidin-4-yl)-4-4.97 (m, 1 H), 4.59 (d, J = 8.2 Hz, 1 H), 4.42- RT = 1.96 min. ((R)-1-4.55 (m, 2 H), 3.88 (br. s., 1 H), 1.49 (d, hydroxyethyl)oxazolidin-2- J= 7.0 Hz, 3 H), 0.80 (br. s., 3 H) one 284: (R)-3-(2-(((S)-1-(5- (CD₃OD)8.51 (s, 1H), 8.24(s, 1H), 7.76 (s, HRMS (B) m/z chloro-6-(1,1- 1H),5.13 (m, 1 H), 4.91 (m, 1H), 4.42- 446.1208, difluoroethyl)pyridin-3-4.55 (m, 2H), 4.41 (br. s., 1 H), 2.12 (t, (M + H)⁺, yl)ethyl)amino)-5-J = 7.0 Hz, 3H), 1.22 (m, 6H) RT = 1.85 min. fluoropyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2- one 285: (R)-3-(2-(((S)-1-(5- (CD₃OD)8.22 (d, J = 2.7 Hz, 1 H), 8.11 (d, HRMS (B) m/z chloro-6-(2,2,2- J =2.0 Hz, 1 H), 7.84 (d, J = 2.0 Hz, 1 H), 480.1065,trifluoroethoxy)pyridin-3- 4.89-5.02 (m, 3 H), 4.62 (d, J = 3.5 Hz, 1(M + H)⁺, yl)ethyl)amino)-5- H), 4.42-4.57 (m, 2 H), 3.90 (br. s., 1 H),RT = 2.10 min. fluoropyrimidin-4-yl)-4- 1.52 (d, J = 7.0 Hz, 3 H), 0.85(br. s., 3 H) ((R)-1- hydroxyethyl)oxazolidin-2- one 286:(R)-3-(2-(((S)-1-(2,4- (CD₃OD) 8.21 (d, J = 2.3 Hz, 1 H), 7.36- HRMS (B)m/z dichlorophenyl)ethyl)ami- 7.46 (m, 2 H), 7.24 (dd, J = 8.2, 2.0 Hz,1 415.0741, no)-5-fluoropyrimidin-4-yl)- H), 5.25 (q, J = 6.7 Hz, 1 H),4.59 (br. s., 1 (M + H)⁺, 4-((R)-1- H), 4.40-4.54 (m, 2 H), 3.81 (br.s., 1 H), RT = 2.07 min. hydroxyethyl)oxazolidin-2- 1.47 (d, J = 7.0 Hz,6 H) one 287: (R)-3-(2-(((S)-1-(6- (CD₃OD) 8.40 (d, J = 2.3 Hz, 1 H),8.12 (br. HRMS (B) m/z bromopyridin-3- s., 1 H), 7.75 (dd, J = 8.4, 2.5Hz, 1 H), 7.59 426.0570, yl)ethyl)amino)-5- (d, J = 8.2 Hz, 1 H), 5.17(br. s., 1 H), 5.05 (M + H)⁺, fluoropyrimidin-4-yl)-4- (q, J = 7.0 Hz, 1H), 4.43 (t, J = 8.6 Hz, 1 H), RT = 1.51 min. ((R)-1- 4.00-4.14 (m, 2H), 1.59 (d, J = 7.0 Hz, 3 hydroxyethyl)oxazolidin-2- H), 1.40 (d, J =6.7 Hz, 3 H) one 288: (R)-3-(2-(((S)-1-(4- (CD₃OD) 8.21 (d, J = 3.1 Hz,1 H), 7.38 (t, HRMS (B) m/z chloro-3- J = 8.0 Hz, 1 H), 7.12-7.28 (m, 2H), 4.88- 399.1031, fluorophenyl)ethyl)amino)- 5.00 (m, 1 H), 4.59 (br.s., 1 H), 4.42-4.55 (M + H)⁺, 5-fluoropyrimidin-4-yl)-4- (m, 2 H), 3.89(br. s., 1 H), 1.49 (d, J = 7.0 RT = 1.91 min. ((R)-1- Hz, 3 H), 0.81(br. s., 3 H) hydroxyethyl)oxazolidin-2- one 289: (R)-3-(2-(((R)-1-(5-(CD₃OD) 8.57 (d, J = 2.3 Hz, 1 H), 7.88- HRMS (B) m/z bromopyridin-2-7.97 (m, 2 H), 7.37 (d, J = 8.6 Hz, 1 H), 5.09 426.0574,yl)ethyl)amino)-5- (br. s., 1 H), 4.94 (d, J = 7.0 Hz, 1H), 4.38 (t,(M + H)⁺, fluoropyrimidin-4-yl)-4- J = 8.8 Hz, 1 H), 3.93-4.12 (m, 2 H),1.51 RT = 1.55 min. ((R)-1- (d, J = 7.0 Hz, 3 H), 1.31 (d, J = 6.3 Hz, 3H) hydroxyethyl)oxazolidin-2- one 290: (R)-3-(2-(((S)-1-(3,4- (CD₃OD)8.20 (d, J = 2.7 Hz, 1 H), 7.51 (d, HRMS (B) m/zdichlorophenyl)ethyl)ami- J = 2.0 Hz, 1 H), 7.43 (d, J = 8.2 Hz, 1 H),415.0738, no)-5-fluoropyrimidin-4-yl)- 7.29 (dd, J = 8.4, 1.8 Hz, 1 H),4.87-4.97 (M + H)⁺, 4-((R)-1- (m, 1 H), 4.59 (br. s., 1 H), 4.40-4.55(m, RT = 2.02 min. hydroxyethyl)oxazolidin-2- 2 H), 3.89 (br. s., 1 H),1.49 (d, J = 7.0 Hz, one 6 H) 291: (R)-3-(2-(((S)-1-(6- (CDCl₃) 8.25 (s,1H), 8.22 (m, 1H), 7.51 HRMS (B) m/z chloro-5-fluoropyridin-3- (m, 1H),5.51 (s, 1H), 4.91 (m, 1 H), 4.51 400.0981, yl)ethyl)amino)-5- (m, 2H),4.41 (m, 1 H), 3.62 (m, 1H), 1.45 (M + H)⁺, fluoropyrimidin-4-yl)-4- (d,J = 7.0 Hz, 3 H), 1.01 (br. s., 3H) RT = 1.61 min. ((R)-1-hydroxyethyl)oxazolidin-2- one 292: (R)-3-(2-(((S)-1-(5,6- (CDCl₃) 8.37(s, 1H), 8.15 (m, 1H), 7.76 HRMS (B) m/z dichloropyridin-3- (m, 1H),5.68 (s, 1H), 4.94 (m, 1 H), 4.51 416.0690, yl)ethyl)amino)-5- (m, 2H),4.45 (m, 1 H), 3.68 (m, 1H), 1.58 (M + H)⁺, fluoropyrimidin-4-yl)-4- (d,J = 7.0 Hz, 3 H), 1.01 (br. s., 3H) RT = 1.73 min. ((R)-1-hydroxyethyl)oxazolidin-2- one 293: (R)-3-(2-(((R)-1-(3,5- (cdcl3) 8.43(d, J = 2.0 Hz, 1 H), 8.23 (d, HRMS (B) m/z dichloropyridin-2- J = 2.3Hz, 1 H), 7.72 (d, J = 2.0 Hz, 1 H), 416.0685, yl)ethyl)amino)-5- 6.29(d, J = 7.8 Hz, 1 H), 5.50 (br. s., 1 H), (M + H)⁺,fluoropyrimidin-4-yl)-4- 4.48-4.59 (m, 2 H), 4.37-4.47 (m, 1 H), RT =1.83 min. ((R)-1- 4.24 (br. s., 1 H), 1.48 (d, J = 6.7 Hz, 3 H),hydroxyethyl)oxazolidin-2- 1.22 (d, J = 6.7 Hz, 3 H) one 294:(R)-3-(2-(((S)-1-(3,5- (CDCl₃) 8.42 (d, J = 2.0 Hz, 1 H), 8.22 (d, HRMS(B) m/z dichloropyridin-2- J = 2.7 Hz, 1 H), 7.72 (d, J = 2.0 Hz, 1 H),416.0687, yl)ethyl)amino)-5- 6.22 (d, J = 8.2 Hz, 1 H), 5.51 (br. s., 1H), (M + H)⁺, fluoropyrimidin-4-yl)-4- 4.47-4.67 (m, 2 H), 4.34-4.45 (m,1 H), RT = 1.82 min. ((R)-1- 1.49 (d, J = 7.0 Hz, 3 H), 1.14 (br. s., 3H) hydroxyethyl)oxazolidin-2- one 295: (R)-3-(6-chloro-2- (CDCl₃) 8.43(d, J = 2.0 Hz, 1 H), 7.73 (d, HRMS (B) m/z (((S)-1-(3,5- J = 2.0 Hz, 1H), 7.50 (s, 1 H), 6.39 (d, 432.0391, dichloropyridin-2- J = 7.4 Hz, 1H), 5.52 (br. s., 1 H), 4.72- (M + H)⁺, yl)ethyl)amino)pyrimidin-4- 4.93(m, 1 H), 4.32-4.62 (m, 2 H), 4.13 RT = 2.27 min. yl)-4-((R)-1- (br. s.,1 H), 1.50 (d, J = 6.7 Hz, 3 H), 1.07 hydroxyethyl)oxazolidin-2- (br.s., 3 H) one 296: (R)-3-(6-chloro-2- (CDCl₃) 8.13 (br. s., 1 H), 7.49(s, 1 H), HRMS (B) m/z (((S)-1-(3-fluoro-5-(2,2,2- 7.07 (dd, J = 10.8,2.2 Hz, 1 H), 6.17 (br. s., 480.1066, trifluoroethoxy)pyridin-2- 1 H),5.40 (br. s., 1 H), 4.70-5.04(m, 1 H), (M + H)⁺,yl)ethyl)amino)pyrimidin-4- 4.52 (br. s., 1 H), 4.41 (q, J = 7.8 Hz, 3H), RT = 2.21 min. yl)-4-((R)-1- 4.18 (br. s., 1 H), 1.53 (br. s., 3 H),1.01- hydroxyethyl)oxazolidin-2- 1.18 (m, 3 H) one 297:(R)-3-(2-(((R)-1-(1-(4- (CDCl₃) 8.19 (d, J = 2.7 Hz, 1 H), 7.81 (d, HRMS(B) m/z chlorophenyl)-1H-pyrazol- J = 2.3 Hz, 1 H), 7.59 (d, J = 9.0 Hz,2 H), 447.1348, 3-yl)ethyl)amino)-5- 7.41 (d, J = 9.0 Hz, 2 H), 6.39 (d,J = 2.3 Hz, 1 (M + H)⁺, fluoropyrimidin-4-yl)-4- H), 5.12 (br. s., 1 H),4.25-4.58 (m, 4 H), RT = 2.00 min. ((R)-1- 3.03 (br. s., 1 H), 1.61 (d,J = 7.0 Hz, 3 H), hydroxyethyl)oxazolidin-2- 1.20 (d, J = 6.3 Hz, 3 H)one 298: (R)-3-(2-(((S)-1-(1-(4- (CDCl₃) 8.19 (d, J = 2.0 Hz, 1 H), 7.80(d, HRMS (B) m/z chlorophenyl)-1H-pyrazol- J = 2.0 Hz, 1 H), 7.58 (d, J= 9.0 Hz, 2 H), 447.1345, 3-yl)ethyl)amino)-5- 7.41 (d, J = 9.0 Hz, 2H), 6.39 (d, J = 2.3 Hz, 1 (M + H)⁺, fluoropyrimidin-4-yl)-4- H), 5.18(br. s., 1 H), 4.60 (t, J = 5.5 Hz, 1 RT = 1.98 min. ((R)-1- H), 4.51(t, J = 8.6 Hz, 1 H), 4.34 (dd, J = 8.8, hydroxyethyl)oxazolidin-2- 5.3Hz, 1 H), 4.00 (br. s., 1 H), 1.62 (d, one J = 7.0 Hz, 3 H), 1.03 (br.s., 3 H) 299: (R)-3-(2-(((R)-1-(1-(4- (CDCl₃) 8.20 (d, J = 2.7 Hz, 1 H),7.76 (s, 1 HRMS (B) m/z chlorophenyl)-1H- H), 7.45 (d, J = 8.6 Hz, 2 H),7.31 (d, J = 8.6 447.1346, imidazol-4-yl)ethyl)amino)- Hz, 2 H), 7.14(s, 1 H), 5.61 (d, J = 7.4 Hz, 1 (M + H)⁺, 5-fluoropyrimidin-4-yl)-4-H), 5.07 (d, J = 5.9 Hz, 1 H), 4.32-4.57 (m, RT = 1.32 min. ((R)-1- 4H), 1.59 (d, J = 6.7 Hz, 3 H), 1.21 (d, hydroxyethyl)oxazolidin-2- J =6.3 Hz, 3 H) one 300: (R)-3-(2-(((S)-1-(1-(4- (CDCl₃) 8.19 (d, J = 2.7Hz, 1 H), 7.71 (s, 1 HRMS (B) m/z chlorophenyl)-1H- H), 7.45 (d, J = 8.6Hz, 2 H), 7.30 (d, J = 8.6 447.1350, imidazol-4-yl)ethyl)amino)- Hz, 2H), 7.12 (s, 1 H), 5.42 (d, J = 7.8 Hz, 1 (M + H)⁺,5-fluoropyrimidin-4-yl)-4- H), 5.20 (quin, J = 7.1 Hz, 1 H), 4.74 (br.s., RT = 1.34 min. ((R)-1- 1 H), 4.54 (t, J = 8.8 Hz, 1 H), 4.29 (dd,hydroxyethyl)oxazolidin-2- J = 8.6, 5.9 Hz, 1 H), 3.99 (br. s., 1 H),1.62 one (d, J = 7.0 Hz, 3 H), 1.15 (d, J = 6.3 Hz, 3 H) 301:(R)-3-(2-(((S)-1-(2,5- (CDCl₃) 8.20 (d, J = 2.7 Hz, 1 H), 7.09 (dd, HRMS(B) m/z difluoro-4-(2,2,2- J = 11.3, 7.0 Hz, 1 H), 6.79 (dd, J = 10.4,6.8 481.1315, trifluoroethoxy)phenyl)eth- Hz, 1 H), 5.52 (br. s., 1 H),5.11(quin, (M + H)⁺, yl)amino)-5- J = 6.7 Hz, 1 H), 4.45-4.59 (m, 2 H),4.31- RT = 2.04 min. fluoropyrimidin-4-yl)-4- 4.44 (m, 3 H), 3.87 (br.s., 1 H), 1.53 (d, ((R)-1- J = 7.0 Hz, 3 H), 1.03 (d, J = 4.3 Hz, 3 H)hydroxyethyl)oxazolidin-2- one 302: (R)-3-(5-fluoro-2- (CDCl₃) 8.19 (d,J = 2.3 Hz, 1 H), 6.62- HRMS (B) m/z (((S)-1-(2-fluoro-4-(2,2,2- 6.75(m, 3 H), 5.48 (br. s., 1 H), 5.14 (t, 463.1403,trifluoroethoxy)phenyl)eth- J = 6.8 Hz, 1 H), 4.43-4.54 (m, 2 H), 4.24-(M + H)⁺, yl)amino)pyrimidin-4-yl)-4- 4.40 (m, 3 H), 3.82 (br. s., 1 H),1.53 (d, RT = 2.03 min. ((R)-1- J = 6.7 Hz, 3 H), 0.99 (br. s., 3 H)hydroxyethyl)oxazolidin-2- one 303: (R)-3-(5-fluoro-2- (CDCl₃) 8.20 (d,J = 2.3 Hz, 1 H), 7.12 (dd, HRMS (B) m/z (((S)-1-(3-fluoro-4-(2,2,2- J =11.7, 2.0 Hz, 1 H), 7.04-7.09 (m, 1 H), 463.1403,trifluoroethoxy)phenyl)eth- 6.93-7.03 (m, 1 H), 5.44 (br. s., 1 H), 4.86(M + H)⁺, yl)amino)pyrimidin-4-yl)-4- (d, J = 6.3 Hz, 1 H), 4.45-4.55(m, 1 H), RT = 1.99 min. ((R)-1- 4.27-4.45 (m, 3 H), 3.76 (br. s., 1 H),1.51 hydroxyethyl)oxazolidin-2- (d, J = 7.0 Hz, 3 H), 1.01 (br. s., 3H)one 304: (R)-3-(5-fluoro-2- (CDCl₃) 8.22 (d, J = 2.7 Hz, 1 H), 7.77 (d,HRMS (B) m/z (((S)-1-(1-(4-fluorophenyl)- J = 2.3 Hz, 1 H), 7.54-7.67(m, 2 H), 7.14 431.1643, 1H-pyrazol-3- (t, J = 8.4 Hz, 2 H), 6.36 (d, J= 2.3 Hz, 1 H), (M + H)⁺, yl)ethyl)amino)pyrimidin-4- 5.66 (d, J = 7.8Hz, 1 H), 5.10-5.25 (m, 1 RT = 1.80 min. yl)-4-((R)-1- H), 4.55-4.64 (m,1 H), 4.47-4.54 (m, 1 hydroxyethyl)oxazolidin-2- H), 4.34 (dd, J = 8.6,5.1 Hz, 1 H), 4.02 (br. one s., 1 H), 1.61 (d, J = 7.0 Hz, 6 H) 305:(R)-3-(5-fluoro-2- (CDCl₃) 8.30 (d, J = 2.7 Hz, 1 H), 8.20 (d, HRMS (B)m/z (((S)-1-(5-(2,2,2- J = 2.7 Hz, 1 H), 7.23-7.37 (m, 2 H), 5.96-446.1449, trifluoroethoxy)pyridin-2- 6.10 (m, 1 H), 4.97-5.14 (m, 1H),4.44- (M + H)⁺, yl)ethyl)amino)pyrimidin-4- 4.57 (m, 2 H), 4.28-4.44 (m,3 H), 3.96 RT = 1.58 min. yl)-4-((R)-1- (br. s., 1 H), 1.54 (d, J = 6.7Hz, 6 H) hydroxyethyl)oxazolidin-2- one 306: (R)-3-(5-fluoro-2- (CDCl₃)8.28 (d, J = 2.3 Hz, 1 H), 8.20 (d, HRMS (B) m/z (((R)-1-(5-(2,2,2- J =3.1 Hz, 1 H), 7.21-7.36 (m, 2 H), 6.02 446.1447,trifluoroethoxy)pyridin-2- (d, J = 6.7 Hz, 1 H), 5.00 (br. s., 1H),4.25- (M + H)⁺, yl)ethyl)amino)pyrimidin-4- 4.57 (m, 5 H), 1.52 (d, J =6.7 Hz, 3 H), 1.20 RT = 1.59 min. yl)-4-((R)-1- (d, J = 6.3 Hz, 3 H)hydroxyethyl)oxazolidin-2- one 307: (R)-3-(2-(((S)-1-(1-(4- (CD₃OD) 9.02(br. s., 1 H), 8.20 (d, J = 6.7 HRMS (B) m/z chlorophenyl)-1H- Hz, 1 H),7.89 (s, 1 H), 7.64-7.72 (m, 3 429.1438, imidazol-4- H), 7.56-7.64 (m, 2H), 5.37 (d, J = 6.3 Hz, (M + H)⁺, yl)ethyl)amino)pyrimidin-4- 1 H),4.75-5.01 (m, 2 H), 4.56 (dd, J = 9.4, RT = 1.30 min. yl)-4-((R)-1- 2.3Hz, 1 H), 4.40-4.50 (m, 1 H), 1.72 (d, hydroxyethyl)oxazolidin-2- J =7.0 Hz, 3 H), 1.02 (d, J = 6.3 Hz, 3 H) one 308: (R)-3-(2-(((S)-1-(1-(4-(CD₃OD) 8.19 (d, J = 2.3 Hz, 1 H), 8.15 (d, HRMS (B) m/zchlorophenyl)-1H-pyrazol- J = 7.0 Hz, 1 H), 7.74 (dd, J = 7.8, 6.7 Hz, 3429.1441, 3-yl)ethyl)amino)pyrimidin- H), 7.45 (d, J = 9.0 Hz, 2 H),6.53(d, J = 2.3 (M + H)⁺, 4-yl)-4-((R)-1- Hz, 1 H), 5.46 (br. s., 1 H),4.81-4.97 (m, RT = 1.65 min. hydroxyethyl)oxazolidin-2- 2 H), 4.60 (dd,J = 9.4, 2.3 Hz, 1 H), 4.42- one 4.53 (m, 1 H), 4.32 (br. s., 1 H), 1.69(d, J = 7.0 Hz, 3H), 0.91 (br. s., 3 H) 309: (R)-3-(6-chloro-2- (CD₃OD)9.34 (s, 1 H), 7.95 (s, 1 H), 7.67- HRMS (B) m/z (((S)-1-(1-(4- 7.75 (m,2 H), 7.60-7.67 (m, 2 H), 7.44 463.1056, chlorophenyl)-1H- (s, 1 H),5.34 (br. s., 1 H), 4.75-4.88 (m, 2 (M + H)⁺, imidazol-4- H), 4.52 (d, J= 9.8 Hz, 1 H), 4.36-4.45 (m, RT = 1.68 min. yl)ethyl)amino)pyrimidin-4-1 H), 1.68 (d, J = 7.0 Hz, 3 H), 0.99 (br. s., yl)-4-((R)-1- 3 H)hydroxyethyl)oxazolidin-2- one 310: (R)-3-(6-chloro-2- (cd3od) 8.04 (d,J = 2.3 Hz, 1 H), 7.71 (dd, HRMS (B) m/z (((S)-1-(1-(4-fluorophenyl)- J= 9.0, 4.7 Hz, 2 H), 7.35 (s, 1 H), 7.19 (t, 447.1346, 1H-pyrazol-3- J =8.8 Hz, 2 H), 6.43 (d, J = 2.7 Hz, 1 H), (M + H)⁺,yl)ethyl)amino)pyrimidin-4- 5.29 (q, J = 7.0 Hz, 1 H), 4.79-4.87 (m, 2RT = 2.18 min. yl)-4-((R)-1- H), 4.52 (dd, J = 9.2, 2.5 Hz, 1 H), 4.35-hydroxyethyl)oxazolidin-2- 4.44 (m, 1 H), 1.59 (d, J = 7.0 Hz, 3 H),0.85 one (br. s., 3 H) 311: (R)-3-(2-(((S)-1-(2,4- (CD₃OD) 8.15 (d, J =6.7 Hz, 1 H), 7.70 (d, HRMS (B) m/z dichlorophenyl)ethyl)ami- J = 7.0Hz, 1 H), 7.51 (d, J = 2.0 Hz, 1 H), 397.0834,no)pyrimidin-4-yl)-4-((R)-1- 7.46 (d, J = 8.6 Hz, 1 H), 7.34 (dd, J =8.6, 2.0 (M + H)⁺, hydroxyethyl)oxazolidin-2- Hz, 1 H), 5.47 (d, J = 5.1Hz, 1 H), 4.57 (dd, RT = 1.77 min. one J = 9.0, 2.3 Hz, 2 H), 4.33-4.50(m, 2 H), 3.80 (br. s., 2 H), 1.58 (d, J = 7.0 Hz, 6 H) 312:(R)-3-(2-(((S)-1-(3,4- (CD₃OD) 8.13 (d, J = 6.7 Hz, 1 H), 7.70 (d, HRMS(B) m/z dichlorophenyl)ethyl)ami- J = 7.0 Hz, 1 H), 7.57 (d, J = 2.0 Hz,1 H), 397.0831, no)pyrimidin-4-yl)-4-((R)-1- 7.51 (d, J = 8.2 Hz, 1 H),7.33 (dd, J = 8.4, 2.2 (M + H)⁺, hydroxyethyl)oxazolidin-2- Hz, 1 H),5.19 (br. s., 1 H), 4.75-5.00 (m, RT = 1.72 min. one 2 H), 4.58 (dd, J =9.4, 2.3 Hz, 1 H), 4.34- 4.51 (m, 1 H), 3.92 (br. s., 1 H), 1.59 (d, J =6.7 Hz, 6 H) 313: (R)-3-(6-chloro-2- (CDCl₃) 7.80 (d, J = 2.3 Hz, 1 H),7.56 (d, HRMS (B) m/z (((S)-1-(1-(4- J = 8.6 Hz, 2 H), 7.51 (s, 1 H),7.42 (d, 463.1056, chlorophenyl)-1H-pyrazol- J = 8.6 Hz, 3 H), 6.39 (d,J = 2.3 Hz, 1H), (M + H)⁺, 3-yl)ethyl)amino)pyrimidin- 6.08 (br. s., 1H), 5.22 (br. s., 1 H), 4.76 RT = 2.34 min. 4-yl)-4-((R)-1- (ddd, J =7.9, 5.0, 2.3 Hz, 1 H), 4.40-4.49 hydroxyethyl)oxazolidin-2- (m, 1 H),4.31-4.39 (m, 1 H), 3.99 (br. s., one 1 H), 1.61 (d, J = 7.0 Hz, 6 H)314: (R)-3-(2-(((S)-1-(2,5- (CDCl₃) 10.88 (br. s., 1 H), 7.93 (d, J =7.0 HRMS (B) m/z difluoro-4-(2,2,2- Hz, 1 H), 7.75 (d, J = 7.0 Hz, 1 H),7.20- 463.1410, trifluoroethoxy)phenyl)eth- 7.30 (m, 1 H), 6.83 (dd, J =10.6, 6.7 Hz, 1 (M + H)⁺, yl)amino)pyrimidin-4-yl)-4- H), 5.34 (t, J =6.8 Hz, 1 H), 4.85 (ddd, RT = 1.79 min. ((R)-1- J = 7.4, 4.7, 2.0 Hz, 1H), 4.61 (dd, J = 9.4, hydroxyethyl)oxazolidin-2- 2.0 Hz, 1 H),4.34-4.52 (m, 3 H), 3.78- one 3.96 (m, 1 H), 1.61(d, J = 7.0 Hz, 3 H),0.96 (d, J = 6.3 Hz, 3 H) 315: (R)-3-(2-(((S)-1-(2- (CDCl₃) 10.61 (d, J= 4.7 Hz, 1 H), 7.98 (d, HRMS (B) m/z fluoro-4-(2,2,2- J = 5.5 Hz, 1 H),7.75 (d, J = 5.9 Hz, 1 H), 445.1492, trifluoroethoxy)phenyl)eth- 7.41(t, J = 8.8 Hz, 1 H), 6.64-6.85(m, 2 H), (M + H)⁺,yl)amino)pyrimidin-4-yl)-4- 5.39 (t, J = 6.5 Hz, 1 H), 4.85 (ddd, J =7.6, RT = 1.74 min. ((R)-1- 4.9, 2.0 Hz, 1 H), 4.60 (dd, J = 9.8, 2.0Hz, 1 hydroxyethyl)oxazolidin-2- H), 4.40-4.50 (m, 1 H), 4.35 (q, J =8.2 Hz, one 2 H), 3.79-3.96 (m, 1 H), 1.61 (d, J = 7.0 Hz, 3 H), 0.94(d, J = 6.3 Hz, 3 H) 316: (R)-3-(2-(((S)-1-(3- (cdcl3) 10.84 (d, J = 3.9Hz, 1 H), 7.92 (d, HRMS (B) m/z fluoro-4-(2,2,2- J = 7.0 Hz, 1 H), 7.73(d, J = 7.0 Hz, 1 H), 445.1491, trifluoroethoxy)phenyl)eth- 7.09-7.20(m, 2 H), 6.97-7.10 (m, 1 H), (M + H)⁺, yl)amino)pyrimidin-4-yl)-4- 4.93(t, J = 6.7 Hz, 1 H), 4.78 (td, J = 5.1, 2.3 RT = 1.69 min. ((R)-1- Hz,1 H), 4.56 (dd, J = 9.4, 2.0 Hz, 1 H), hydroxyethyl)oxazolidin-2-4.35-4.47 (m, 3 H), 3.64-3.75 (m, 1 H), one 1.62 (d, J = 7.0 Hz, 3 H),0.94 (d, J = 6.3 Hz, 3 H) 317: (R)-3-(2-(((S)-1-(5- (CDCl₃) 11.02 (d, J= 6.7 Hz, 1 H), 8.59 (d, HRMS (B) m/z bromopyridin-2- J = 1.6 Hz, 1 H),8.03 (dd, J = 8.4, 1.8 Hz, 1 408.0668, yl)ethyl)amino)pyrimidin-4- H),7.94 (d, J = 6.7 Hz, 1 H), 7.76(d, J = 6.7 (M + H)⁺, yl)-4-((R)-1- Hz, 1H), 7.58 (d, J = 8.6 Hz, 1 H), 5.40 (t, RT = 1.29 min.hydroxyethyl)oxazolidin-2- J = 7.0 Hz, 1 H), 4.83-4.95 (m, 1 H), 4.62one (dd, J = 9.4, 1.6 Hz, 1 H), 4.40-4.51 (m, 1 H), 3.70-3.84 (m, 1 H),1.70 (d, J = 7.0 Hz, 3H), 1.02 (d, J = 6.3 Hz, 3 H) 318:(R)-3-(2-(((R)-1-(5- (CDCl₃) 10.97 (d, J = 4.3 Hz, 1 H), 8.62 (d, HRMS(B) m/z bromopyridin-2- J = 1.6 Hz, 1 H), 8.09 (dd, J = 8.2, 1.6 Hz, 1408.0670, yl)ethyl)amino)pyrimidin-4- H), 7.99 (d, J = 6.7 Hz, 1 H),7.77(d, J = 6.7 (M + H)⁺, yl)-4-((R)-1- Hz, 1 H), 7.63 (d, J = 8.2 Hz, 1H), 5.37 (t, RT = 1.33 min. hydroxyethyl)oxazolidin-2- J = 6.5 Hz, 1 H),4.59-4.74 (m, 2 H), 4.29- one 4.46 (m, 2 H), 1.70 (d, J = 6.7 Hz, 3 H),1.17 (d, J = 6.3 Hz, 3 H) 319: (R)-3-(2-(((S)-1-(4,5- (CD₃OD) 8.15 (d, J= 7.0 Hz, 1 H), 7.70 (d, HRMS (B) m/z dichloro-2- J = 6.3 Hz, 1 H), 7.58(d, J = 7.0 Hz, 1 H), 415.0733, fluorophenyl)ethyl)amino) 7.41 (d, J =9.8 Hz, 1 H), 5.42 (d, J = 3.5 Hz, 1 (M + H)⁺, pyrimidin-4-yl)-4-((R)-1-H), 4.87 (d, J = 5.5 Hz, 2 H), 4.58 (dd, RT = 1.84 min.hydroxyethyl)oxazolidin-2- J = 9.0, 2.3 Hz, 1 H), 4.38-4.50 (m, 1 H),one 3.91 (br. s., 1 H), 1.60 (d, J = 7.0 Hz, 3 H), 0.84 (br. s., 3H)320: (R)-3-(2-(((S)-1-(2,5- (CD₃OD) 9.26 (s, 1 H), 8.19 (d, J = 7.0 Hz,HRMS (B) m/z difluoro-4-(4-methyl-1H- 1 H), 7.77 (d, J = 6.7 Hz, 1 H),7.54-7.71 445.1794, imidazol-1- (m, 3 H), 5.51 (d, J = 5.9 Hz, 1 H),4.81- (M + H)⁺, yl)phenyl)ethyl)amino)pyrim- 4.90 (m, 1 H), 4.58 (dd, J= 9.2, 2.2 Hz, 1 RT = 1.02 min. idin-4-yl)-4-((R)-1- H), 4.41-4.51 (m, 1H), 3.75 (br. s., 1 H), hydroxyethyl)oxazolidin-2- 2.44 (s, 3 H), 1.66(d, J = 6.7 Hz, 3 H), 0.87 one (br. s., 3 H) 321: (R)-3-(5-chloro-2-(CD₃OD) 8.20 (s, 1 H), 7.43 (d, J = 7.0 Hz, HRMS (B) m/z(((S)-1-(4,5-dichloro-2- 1 H), 7.26 (d, J = 9.4 Hz, 1 H), 5.11 (br. s.,1 449.0347, fluorophenyl)ethyl)amino) H), 4.68-4.90 (m, 1 H), 4.43 (t, J= 8.2 Hz, 1 (M + H)⁺, pyrimidin-4-yl)-4-((R)-1- H), 4.25-4.37 (m, 1 H),3.44-3.86 (m, 1 RT = 2.14 min. hydroxyethyl)oxazolidin-2- H), 1.42 (d, J= 7.0 Hz, 3 H), 0.73 (br. s., 3 one H) 322: (R)-3-(2-(((S)-1-(2,5-(CD₃OD) 8.74 (d, J = 6.3 Hz, 1 H), 8.11- HRMS (B) m/z difluoro-4-(2-8.22 (m, 2 H), 8.07 (d, J = 6.3 Hz, 1 H), 7.59- 456.1840,methylpyridin-4- 7.77 (m, 2 H), 7.40-7.53 (m, 1H), 5.48 (M + H)⁺,yl)phenyl)ethyl)amino)pyrim- (d, J = 5.5 Hz, 1 H), 4.77-5.01 (m, 2 H),RT = 1.10 min. idin-4-yl)-4-((R)-1- 4.57 (dd, J = 9.0, 2.3 Hz, 1 H),4.38-4.51 hydroxyethyl)oxazolidin-2- (m, 1 H), 2.83 (s, 3 H), 1.66 (d, J= 7.0 Hz, 2 one H), 0.82 (br. s., 3 H) 323: (R)-3-(2-(((S)-1-(2,5-(CD₃OD) 8.91 (s, 1 H), 8.60 (d, J = 8.2 Hz, HRMS (B) m/z difluoro-4-(6-1 H), 8.18 (d, J = 6.3 Hz, 1 H), 7.95 (d, 456.1847, methylpyridin-3- J =8.2 Hz, 1 H), 7.73 (d, J = 6.3 Hz, 1H), (M + H)⁺,yl)phenyl)ethyl)amino)pyrim- 7.54 (dd, J = 10.2, 6.7 Hz, 1 H), 7.42 (dd,RT = 1.18 min. idin-4-yl)-4-((R)-1- J = 10.8, 6.1 Hz, 1 H), 5.49 (d, J =4.7 Hz, 1 hydroxyethyl)oxazolidin-2- H), 4.88 (s, 1 H), 4.58 (dd, J =9.2, 2.2 Hz, 1 one H), 4.39-4.51(m, 1 H), 3.83 (br. s., 1 H), 2.82 (s, 3H), 1.66 (d, J = 7.0 Hz, 3 H), 0.83 (br. s., 3 H) 324:(R)-3-(2-(((S)-1-(2,5- (CD₃OD) 8.80 (d, J = 5.1 Hz, 1 H), 8.18 (d, HRMS(B) m/z difluoro-4-(2- J = 6.7 Hz, 1 H), 7.97-8.07 (m, 1 H), 7.77-510.1560, (trifluoromethyl)pyridin-4- 7.90 (m, 2 H), 7.54 (dd, J = 10.6,6.3 Hz, 1 (M + H)⁺, yl)phenyl)ethyl)amino)pyrim- H), 7.40 (dd, J = 11.0,6.3 Hz, 1 H), 5.49 (br. RT = 1.94 min. idin-4-yl)-4-((R)-1- s., 1 H),4.79-5.02 (m, 1 H), 4.53-4.68 hydroxyethyl)oxazolidin-2- (m, 1 H),4.39-4.52 (m, 1 H), 3.80 (br. s., one 1 H), 1.61-1.73 (m, 6 H) 325:(R)-3-(2-(((S)-1-(2,5- (CD₃OD) 8.90 (s, 1 H), 8.12-8.29 (m, 2 HRMS (B)m/z difluoro-4-(6- H), 7.92 (d, J = 8.2 Hz, 1 H), 7.75 (d, J = 6.7510.1565, (trifluoromethyl)pyridin-3- Hz, 1 H), 7.43-7.55 (m, 1 H),7.37(dd, (M + H)⁺, yl)phenyl)ethyl)amino)pyrim- J = 10.8, 6.1 Hz, 1 H),5.47 (br. s., 1 H), RT = 1.98 min. idin-4-yl)-4-((R)-1- 4.81-4.97 (m, 1H), 4.58 (dd, J = 9.0, 2.3 hydroxyethyl)oxazolidin-2- Hz, 1 H),4.39-4.51 (m, 1 H), 3.82 (br. s., one 1 H), 1.66 (d, J = 7.0 Hz, 3 H),0.82 (br. s., 3 H) 326: (R)-4-((R)-1- HRMS (B) m/zhydroxyethyl)-3-(2-(((S)-1- 401.2188 (4-isobutoxyphenyl)eth- (M + H)⁺;yl)amino)pyrimidin-4- Rt 1.80 min yl)oxazolidin-2-one 327:(R)-3-(5-fluoro-2- (CD₃OD) 8.22 (d, J = 3.13 Hz, 1H), 7.14- HRMS (B) m/z(((S)-1-(2-fluoro-4- 7.41 (m, 1H), 6.55-6.79 (m, 2H), 5.19 (q, 395.1525methoxyphenyl)- J = 7.04 Hz, 1H), 4.68 (d, J = 3.91 Hz, 1H), (M + H)⁺;ethyl)amino)pyrimidin-4- 4.43-4.60 (m, 2H), 3.92 (d, J = 17.22 Hz, Rt1.78 min yl)-4-((R)-1-hydroxy- 1H), 3.78 (s, 3H), 1.50 (d, J = 6.65 Hz,3H) ethyl)oxazolidin-2-one 328: (R)-3-(2-(((S)-1-(2,3- 1H NMR (400 MHz,<cd3od>) 0.83 (br. s., HRMS (B) m/z difluorophenyl)ethyl)ami- 3 H) 1.60(d, J = 6.65 Hz, 3 H) 4.40-4.45 365.1414, no)pyrimidin-4-yl)-4-((R)-1-(m, 1 H) 4.56 (d, J = 7.43 Hz, 1 H) 4.85 (m, (M + H)⁺,hydroxyethyl)oxazolidin-2- 2H) 5.39-5.47 (m, 1 H) 7.11-7.21 (m, 3 RT =1.49 min. one H) 7.61-7.68 (m, 1 H) 8.12 (d, J = 6.65 Hz, 1 H) 329:(R)-3-(2-(((S)-1-(2,3- 1H NMR (400 MHz, <cd3od>) 0.81 (br. s., HRMS (B)m/z difluorophenyl)ethyl)amino)- 3 H) 1.52 (d, J = 7.04 Hz, 3 H)3.81-3.96 383.1327, 5-fluoropyrimidin-4-yl)-4- (m, 1 H) 4.44-4.56 (m, 2H) 4.57-4.68 (M + H)⁺, ((R)-1- (m, 1 H) 5.21-5.32 (m, 1 H) 7.01-7.22 RT= 1.81 min. hydroxyethyl)oxazolidin-2- (m, 3H) 8.21 (d, J = 3.08 Hz, 1H) one 330: (R)-3-(2-(((S)-1-(3,4- 1H NMR (400 MHz, <cd3od>) 0.83 (br.s., HRMS (B) m/z difluorophenyl)ethyl)ami- 3 H) 1.48 (d, J = 7.04 Hz, 3H) 3.81-3.97 383.1328, no)-5-fluoropyrimidin-4-yl)-4- (m, 1 H) 4.39-4.57(m, 2 H) 4.59-4.68 (M + H)⁺, ((R)-1- (m, 1 H) 4.89-5.01 (m, 2 H)7.11-7.32 (m, 3 RT = 1.81 min. hydroxyethyl)oxazolidin-2- H) 8.21 (d, J= 3.13 Hz, 1 H) one 331: (R)-3-(2-(((S)-1-(2,4- 1H NMR (400 MHz,<cd3od>) 0.73 (br. s., HRMS (B) m/z difluorophenyl)ethyl)ami- 3 H) 1.41(d, J = 6.99 Hz, 3 H) 3.81 (br. s., 383.1323,no)-5-fluoropyrimidin-4-yl)-4- 1 H) 4.32-4.47 (m, 2 H) 4.54 (d, J = 3.03(M + H)⁺, ((R)-1- Hz, 1 H) 5.11 (d, J = 6.94 Hz, RT = 1.80 min.hydroxyethyl)oxazolidin-2- 1 H) 6.73-6.89 (m, 2 H) 7.29 (td, J = one8.57, 6.53 Hz, 1 H) 8.11 (d, J = 2.98 Hz, 1 H) 332:(R)-3-(2-(((S)-1-(3,5- HRMS (B) m/z difluorophenyl)ethyl)amino)-383.1328, 5-fluoropyrimidin-4-yl)-4- (M + H)⁺, ((R)-1- RT = 1.81 min.hydroxyethyl)oxazolidin-2- one 333: (R)-3-(5-chloro-2- 1H NMR (400 MHz,<cd3od>) 1.26-1.39 LCMS m/z (((S)-1-(5-(2- (m, 3 H) 1.61 (d, J = 7.04Hz, 3 H) 4.74- 509.2, (M + H)⁺, (trifluoromethyl)pyridin-4- 4.79 (m, 3H) 4.96 (br. s., 1 H) 5.13 (d, RT = 0.69 min. yl)pyrimidin-2- J = 7.04Hz, 1 H) 7.69 (d, J = 7.83 Hz, 1 H) yl)ethyl)amino)pyrimidin-4- 7.99 (d,J = 4.30 Hz, 1 H) 8.17 (s, 1 H) 8.29 yl)-4-((R)-1- (d, J = 8.22 Hz, 1 H)8.80 (d, J = 5.09 Hz, 1 hydroxyethyl)oxazolidin-2- H) 8.96 (s, 1 H) one

Example 334(R)-3-(5-fluoro-2-(((S)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

To(R)-3-(2-(((S)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one(20 mg, 0.042 mmol) in MeOH (10 mL) was added Pd(OH)₂ (10 mg, 0.014mmol). The reaction was purged with N₂ and H₂ three times each. Ahydrogen balloon was applied to the reaction. The reaction mixture wasstirred for one hour and concentrated. The residue was applied directlyto HPLC separation to give product (15 mg) as a trifluoroacetic acidsalt. 1HNMR (CD3OD) δ ppm 8.21 (d, J=3.1 Hz, 1H), 7.38 (t, J=8.0 Hz,1H), 7.12-7.28 (m, 2H), 4.88-5.00 (m, 1H), 4.59 (br. s., 1H), 4.42-4.55(m, 2H), 3.89 (br. s., 1H), 1.49 (d, J=7.0 Hz, 3H), 0.81 (br. s., 3H).HRMS (B) m/z 446.1448 (M+H)⁺, RT=1.90 min.

Example 335(R)-3-(2-((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethylamino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

A mixture of(R)-4-((R)-1-tert-butoxyethyl)-3-(2-chloro-5-fluoropyrimidin-4-yl)oxazolidin-2-one(40 mg, 0.126 mmol), (S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethanamine(36.9 mg, 0.164 mmol) and Huenig's base (0.11 mL, 0.629 mmol) in DMSO(0.25 mL) under argon atmosphere was heated at ˜120° C. for ˜16 hr in asealed vial. The mixture was allowed to cool to room temperature anddiluted with ethyl acetate and water. The aqueous layer was extractedwith ethyl acetate (2×), the combined organic layers were washed withbrine and dried over sodium sulfate, filtered off and concentrated underreduced pressure. The residue was dissolved in DCM (0.8 mL) and cooledto 0° C. To the mixture was added trifluoroacetic acid (0.3 mL), theice-bath was removed and the mixture was stirred for ˜1 hr at roomtemperature. The mixture was diluted with methanol (2 mL) andconcentrated under reduced pressure. The residue was dissolved inDMSO/water (˜9/1), filtered through a syringe filter, and purified byreverse phase HPLC. Selected fractions were collected and lyophilizedproviding(R)-3-(2-((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethylamino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-oneas its trifluoroacetic acid salt (19 mg) as a white solid.

¹H NMR (400 Mhz, CD₃OD) δ ppm 9.77 (d, J=2.7 Hz, 1H), 9.06 (t, J=7.8 Hz,1H), 8.80-8.87 (m, 2H), 8.12-8.44 (m, 1H), 6.82 (q, J=6.7 Hz, 1H),6.12-6.21 (m, 1H), 5.99-6.11 (m, 2H), 5.30-5.52 (m, 1H), 3.09 (d, J=7.0Hz, 3H), 2.14-2.51 (m, 3H). HRMS m/z 415.1390 (M+H)+; Rt-1.84 min.

The following Example was prepared using a method similar to thatdescribed for the preparation of Example 335

Example 336(R)-3-(2-(((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

¹H NMR (400 Mhz, CCl₃D) δ ppm 8.19 (d, J=2.7 Hz, 1H), 7.33-7.44 (m, 1H),7.18-7.30 (m, 2H), 5.49 (m, J=5.9 Hz, 1H), 5.19 (m, J=6.7, 6.7 Hz, 1H),4.41-4.52 (m, 2H), 4.34 (m, J=7.2, 3.7 Hz, 1H), 1.90 (t, J=18.2 Hz, 3H),1.51-1.60 (m, 3H), 0.80-1.00 (m, 3H). HRMS m/z 429.1553 (M+H)+; Rt-1.98min.

Example 337(R)-3-(6-chloro-2-(((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

A mixture of(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one(55 mg, 0.165 mmol), (S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethanaminehydrochloride (35 mg, 0.155 mmol) and Huenig's base (0.072 mL, 0.411mmol) in DMSO (0.6 mL) under argon atmosphere was heated at ˜85° C. for˜3 hr in a sealed vial. The mixture was allowed to cool to roomtemperature and diluted with ethyl acetate and water. The aqueous layerwas extracted with ethyl acetate (2×), the combined organic layers werewashed with brine and dried over sodium sulfate, filtered off andconcentrated under reduced pressure. The residue was dissolved in DCM(0.8 mL) and cooled to 0° C. To the mixture was added trifluoroaceticacid (0.4 mL), the ice-bath was removed and the mixture was stirred for˜1 hr at room temperature. The mixture was diluted with methanol (2 mL)and concentrated under reduced pressure. The residue was dissolved inDMSO/water (˜9/1), filtered through a syringe filter, and purified byreverse phase HPLC. Selected fractions were collected and lyophilizedproviding(R)-3-(6-chloro-2-(((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-oneas its trifluoroacetic acid salt (8.2 mg) as a white solid.

¹H NMR (400 Mhz, CD₃OD) δ ppm 7.50 (m, J=7.60, 7.6 Hz, 1H), 7.25-7.38(m, 3H), 6.76 (t, J=1.0 Hz, 1H), 5.31-5.43 (m, 1H), 4.72-4.81 (m, 1H),4.52 (m, J=7.0 Hz, 1H), 4.34-4.44 (m, 1H), 1.55 (d, J=7.0 Hz, 3H),0.54-0.75 (m, CH₃). HRMS m/z 431.1097 (M+H)+; Rt-2.21 min.

The following Example was prepared using a method similar to thatdescribed for the preparation of Example 337

Example 338(R)-3-(6-chloro-2-(((S)-1-(4-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

¹H NMR (400 Mhz, CD₃OD) δ ppm 7.45 (m, J=7.6, 7.6 Hz, 1H), 7.21-7.36 (m,3H), 5.34 (m, J=7.0 Hz, 1H), 4.71-4.79 (m, 1H), 4.45-4.55 (m, 1H),4.32-4.41 (m, 1H), 1.89 (t, J=18.2 Hz, 3H), 1.52 (d, J=7.0 Hz, 3H),0.55-0.71 (m, CH₃). HRMS m/z 445.1257 (M+H)+; Rt-2.32 min.

Example 339(R)-3-(6-chloro-2-(((S)-1-(5-phenylthiophen-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

A solution of(R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one(0.040 g, 0.144 mmol), (S)-1-(5-(pyridin-2-yl)thiophen-2-yl)ethanaminehydrochloride (0.083 g, 0.346 mmol, 2.4 equiv) andN-ethyl-N-isopropylpropan-2-amine (0.075 mL, 0.432 mmol, 3.0 equiv) inDMSO (0.72 mL) was heated at 100° C. for 1 h. Purification by reversephase HPLC separated the regioisomeric products and provided thetrifluoroacetate salt of(R)-3-(6-chloro-2-(((S)-1-(5-phenylthiophen-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one(7.0 mg, white solid) in 8% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (s,1H), 7.56-7.52 (m, 2H), 7.40-7.34 (m, 2H), 7.29 (d, J=7.4 Hz, 1H), 7.15(d, J=3.6 hz, 1H), 6.93 (br s, 1H), 5.21 (m, 1H), 4.78-4.68 (m, 1H),4.50-4.31 (m, 2H), 3.85 (m, 1H), 1.69 (d, J=6.9 Hz, 3H), 0.93 (br s,3H); HRMS m/z 445.1109 (M+H)⁺; Rt-2.49 min.

The following Example was prepared using a method similar to thatdescribed for the preparation of Example 339

Example 340(R)-3-(6-chloro-2-(((S)-1-(5-(pyridin-2-yl)thiophen-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

¹H NMR (400 MHz, CDCl₃) δ ppm 8.84 (d, J=5.0 Hz, 1H), 8.05 (t, J=7.8 Hz,1H), 7.77-7.70 (m, 2H), 7.60 (s, 1H), 7.47 (t, J=6.5 Hz, 1H), 7.13 (d,J=3.9 Hz, 1H), 5.19 (m, 1H), 4.87 (m, 1H), 4.62 (m, 1H), 4.37 (t, J=9.0Hz, 1H), 3.61 (m, 1H), 1.70 (d, J=7.0 Hz, 3H), 0.89 (br s, 3H). HRMS m/z446.1054 (M+H)⁺; Rt-2.04

Example 341 (1:1 TFA:DCM)

A solution of(R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one(56.5 mg, 0.12 mmol) in DCM (0.6 ml) was treated with TFA (0.6 ml) atroom temperature. The resulting solution was let sit for 2 hours, thenconcentrated. The crude material was purified by reverse phase HPLC.Product fractions were combined and lyophilized to afford(R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one(15.2 mg, 0.036 mmol, 30% yield) as a TFA salt. ¹H NMR (400 MHz,DMSO-d6) δ 0.65 (br. s., 3H) 1.41 (d, J=6.99 Hz, 3H) 1.84-1.94 (m, 1H)2.10-2.22 (m, 1H) 3.67-3.89 (m, 4H) 4.33-4.47 (m, 2H) 4.70-4.77 (m, 1H)4.96 (dd, J=6.06, 4.60 Hz, 1H) 5.01-5.11 (m, 1H) 6.73 (dd, J=8.07, 2.05Hz, 1H) 6.89-6.97 (m, 2H) 7.19 (t, J=7.85 Hz, 1H) 7.24 (d, J=6.06 Hz,1H) 8.14 (br. s., 1H). LCMS m/z 415.3 (M+H)⁺, Rt 0.55 min. HRMS(A) m/z415.1981 (M+H)⁺, Rt 1.33 min.

The compounds in Table 31a were prepared using methods similar to thosedescribed for the preparation of Example 341.

TABLE 31a

342

343

344

345

346

347

348

349

350

351

352

353

354

355

TABLE 31b Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 31a. Example: Name ¹H NMR (400 MHz) d ppm LCMS342: (R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(3- (DMSO-d6) δ 0.93 (s, 3H) HRMS m/z isobutoxyphenyl)ethylamino)pyrimidin-4- 0.95 (s, 3 H) 1.41(d, J = 6.99 401.2189 yl)oxazolidin-2-one Hz, 3 H) 1.96 (dquin, J =13.30, (M + H)⁺; 6.64, 6.64, 6.64, 6.64 Hz, 1 H) Rt-1.86 min 3.55-3.89(m, 4 H) 4.34-4.41 (m, 1 H) 4.42-4.48 (m, 1 H) 4.71-4.78 (m, 1 H) 5.06(br. s., 1 H) 6.73 (dd, J = 8.14, 1.93 Hz, 1 H) 6.87-6.99 (m, 2 H) 7.17(t, J = 7.87 Hz, 1 H) 7.23 (d, J = 6.02 Hz, 1 H) 8.13 (br. s., 1 H) 343:(R)-3-(6-chloro-2-(((S)-1-(4- (DMSO-d6) δ 0.55 (d, J = 6.31 HRMS m/z(isobutylsulfonyl)phenyl)ethyl)amino)pyrimidin- Hz, 3 H) 0.94 (dd, J =6.70, 1.91 483.1472 4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one Hz, 6H) 1.43 (d, J = 6.85 Hz, 3 (M + H)⁺; H) 1.97 (dt, J = 13.11, 6.70 Hz,Rt-2.10 min 1 H) 3.14 (d, J = 6.36 Hz, 2 H) 4.31-4.49 (m, 3 H) 4.71 (br.s., 1 H) 5.09 (t, J = 7.19 Hz, 1 H) 7.17 (s, 1 H) 7.61 (d, J = 8.22 Hz,2 H) 7.83 (d, J = 8.31 Hz, 2 H) 8.49 (d, J = 7.78 Hz, 1 H) 344:(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4- (DMSO-d6) δ 0.59 (br. s., 3H) HRMS m/z (trifluoromethoxy)phenyl)ethyl)amino)pyrimidin- 1.44 (d, J =6.99 Hz, 3 H) 3.83 413.1435 4-yl)oxazolidin-2-one (br. s., 1 H)4.34-4.41 (m, 1 (M + H)⁺; H) 4.41-4.47 (m, 1 H) 4.70- Rt-1.72 min 4.76(m, 2 H) 5.09 (quin, J = 7.24 Hz, 1 H) 7.24 (d, J = 6.02 Hz, 1 H) 7.28(d, J = 7.97 Hz, 2 H) 7.49 (d, J = 8.61 Hz, 2 H) 8.16 (br. s., 1 H) 8.24(br. s., 1 H) 345: (R)-3-(2-(((S)-1-(3-fluoro-4- (DMSO-d6) δ 0.57 (br.s., 3 H) HRMS m/z (trifluoromethoxy)phenyl)ethyl)amino)pyrimidin- 1.43(d, J = 7.04 Hz, 3 H) 4.31- 431.13454-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 4.47 (m, 3 H) 4.71 (br. s.,1 H) (M + H)⁺; 5.08 (t, J = 7.16 Hz, 1 H) 7.23 Rt-1.83 min (d, J = 5.87Hz, 1 H) 7.29 (d, J = 8.66 Hz, 1 H) 7.42-7.52 (m, 2 H) 8.09 (br. s., 1H) 8.16 (br. s., 1 H) 346: (R)-3-(2-(((S)-1-(2-fluoro-4- (DMSO-d6) δ0.37-0.66 (m, 3 HRMS m/z (trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-H) 1.43 (d, J = 7.04 Hz, 3 H) 431.13414-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 4.32-4.46 (m, 2 H) 4.71(br. (M + H)⁺; s., 1 H) 5.26 (br. s., 1 H) 7.18 Rt-1.85 min (d, J = 8.51Hz, 1 H) 7.22 (d, J = 5.82 Hz, 1 H) 7.29 (d, J = 10.86 Hz, 1 H) 7.49 (t,J = 8.49 Hz, 1 H) 8.03 (br. s., 1 H) 8.16 (br. s., 1 H) 347:(R)-3-(2-(((S)-1-(4-(difluoromethoxy)-3- (DMSO-d6) δ 0.64 (br. s., 3 H)HRMS m/z fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)- 1.42 (d, J =6.99 Hz, 3 H) 4.34- 413.1436 1-hydroxyethyl)oxazolidin-2-one 4.47 (m, 3H) 4.67-4.78 (m, 1 (M + H)⁺; H) 5.06 (quin, J = 7.27 Hz, 1 H) Rt-1.60min 6.93-7.18 (m, 1 H) 7.19-7.32 (m, 3 H) 7.38 (d, J = 11.84 Hz, 1 H)8.03-8.11 (m, 1 H) 8.15 (br. s., 1 H) 348:(R)-3-(2-(((S)-1-(4-(difluoromethoxy)-3- (DMSO-d6) δ 0.60 (br. s., 3 H)HRMS m/z fluorophenyl)ethyl)amino)-5-fluoropyrimidin-4- 1.41 (d, J =7.04 Hz, 3 H) 4.35- 431.1333 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one4.43 (m, 1 H) 4.45-4.57 (m, 2 (M + H)⁺; H) 4.89 (br. s., 1 H) 6.91-7.17Rt-1.89 min (m, 1 H) 7.17-7.31 (m, 2 H) 7.31-7.41 (m, 1 H) 7.82-8.03 (m,1 H) 8.34 (br. s., 1 H) 349: (R)-3-(2-(((S)-1-(4- (DMSO-d6) δ 0.61 (br.s., 3 H) HRMS m/z (difluoromethoxy)phenyl)ethyl)amino)pyrimidin- 1.37(d, J = 7.04 Hz, 3 H) 4.29- 395.15234-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 4.42 (m, 3 H) 4.65-4.73 (m,1 (M + H)⁺; H) 5.01 (quin, J = 7.20 Hz, 1 H) Rt-1.49 min 7.04 (d, J =8.51 Hz, 2 H) 7.09 (s, 1 H) 7.17 (d, J = 5.92 Hz, 1 H) 7.37 (d, J = 8.51Hz, 2 H) 8.08 (br. s., 1 H) 350:(R)-3-(2-(((S)-1-(4-(difluoromethoxy)-2- (DMSO-d6) δ 0.61 (br. s., 3 H)HRMS m/z fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)- 0.93 (br. s.,1 H) 1.44 (d, 413.1431 1-hydroxyethyl)oxazolidin-2-one J = 6.94 Hz, 3 H)3.76 (br. s., 1 (M + H)⁺; H) 4.34-4.47 (m, 2 H) 4.73 (d, Rt-1.60 min J =3.57 Hz, 1 H) 5.26 (quin, J = 6.90 Hz, 1 H) 6.98 (dd, J = 8.46, 2.20 Hz,1 H) 7.06 (dd, J = 11.20, 2.30 Hz, 1 H) 7.26 (d, J = 5.77 Hz, 1 H) 7.43(t, J = 8.66 Hz, 1 H) 8.17 (br. s., 1 H) 351:(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3- (DMSO-d6) δ 0.60 (br. s., 3H) HRMS m/z (trifluoromethoxy)phenyl)ethyl)amino)pyrimidin- 1.44 (d, J =7.04 Hz, 3 H) 3.87 413.1432 4-yl)oxazolidin-2-one (br. s., 1 H)4.34-4.47 (m, 2 (M + H)⁺; H) 4.71-4.76 (m, 2 H) 5.14 Rt-1.73 min (quin,J = 7.23 Hz, 1 H) 7.13- 7.21 (m, 1 H) 7.25 (d, J = 5.97 Hz, 1 H) 7.34(s, 1 H) 7.38- 7.46 (m, 2 H) 8.16 (br. s., 1 H) 352:(R)-3-(2-(((S)-1-(3- (DMSO-d6) δ 0.63 (br. s., 3 H) HRMS m/z(difluoromethoxy)phenyl)ethyl)amino)pyrimidin- 1.43 (d, J = 7.04 Hz, 3H) 3.85 395.1534 4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (br. s., 4H) 4.35-4.47 (m, 2 (M + H)⁺; H) 4.71-4.76 (m, 1 H) 5.09 Rt-1.52 min(quin, J = 7.30 Hz, 1 H) 6.96- 7.02 (m, 1 H) 7.17 (d, J = 7.48 Hz, 1 H)7.21-7.27 (m, 2 H) 7.31-7.37 (m, 1 H) 8.15 (br. s., 1 H) 353:(R)-3-(2-(((S)-1-(4-(difluoromethoxy)-2- (DMSO-d6) δ 0.33-1.02 (m, 3HRMS m/z fluorophenyl)ethyl)amino)-5-fluoropyrimidin-4- H) 1.40 (d, J =6.99 Hz, 3 H) 431.1334 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one4.32-4.55 (m, 3 H) 5.13 (br. (M + H)⁺; s., 1 H) 6.96 (dd, J = 8.53, 2.37Rt-1.92 min Hz, 1 H) 7.04 (dd, J = 11.10, 2.40 Hz, 1 H) 7.17-7.38 (m, 1H) 7.41 (t, J = 8.58 Hz, 1 H) 7.97 (br. s., 1 H) 8.34 (br. s., 1 H) 354:(R)-3-(5-fluoro-2-(((S)-1-(3- (DMSO-d6) δ 0.15-0.91 (m, 3 HRMS m/z(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin- H) 1.41 (d, J = 7.04 Hz,3 H) 431.1337 4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 4.27-4.56 (m,3 H) 4.94 (br. (M + H)⁺; s., 2 H) 7.15 (d, J = 7.34 Hz, 1 Rt-2.04 min H)7.30 (s, 1 H) 7.34-7.45 (m, 2 H) 7.97 (br. s., 1 H) 8.33 (br. s., 1 H)355: (R)-3-(2-(((S)-1-(3- (DMSO-d6) δ 0.58 (br. s., 3 H) HRMS m/z(difluoromethoxy)phenyl)ethyl)amino)-5- 1.41 (d, J = 7.04 Hz, 3 H) 3.89413.1435 fluoropyrimidin-4-yl)-4-((R)-1- (br. s., 2 H) 4.33-4.57 (m, 3(M + H)⁺; hydroxyethyl)oxazolidin-2-one H) 4.90 (br. s., 1 H) 6.93-7.00Rt-1.83 min (m, 1 H) 7.11-7.18 (m, 1 H) 7.21 (d, J = 7.78 Hz, 1 H) 7.32(t, J = 8.00 Hz, 1 H) 7.93 (br. s., 1 H) 8.32 (br. s., 1 H)

Example 356 (1:3 TFA:DCM)

A solution of(R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-phenoxyphenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one(70.1 mg, 0.147 mmol) in DCM (1.1 ml) was treated with TFA (368 ul) atroom temperature. The resulting solution was let sit for 30 min, thenconcentrated. The crude material was purified by reverse phase HPLC.Product fractions were combined and lyophilized to afford(R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(3-phenoxyphenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one(41.3 mg, 0.097 mmol, 66% yield) as a TFA salt. ¹H NMR (400 MHz,DMSO-d6) δ 0.64 (br. s., 3H) 1.42 (d, J=6.90 Hz, 3H) 3.70 (br. s., 1H)4.32-4.48 (m, 3H) 4.67-4.75 (m, 1H) 5.08 (br. s., 1H) 6.78 (d, J=7.87Hz, 1H) 6.91 (d, J=7.87 Hz, 2H) 7.00-7.18 (m, 3H) 7.22-7.37 (m, 4H) 8.14(br. s., 1H). LCMS m/z 421.3 (M+H)⁺, Rt 0.72 min. HRMS(A) m/z 421.1873(M+H)⁺, Rt 1.84 min.

The compounds in Table 32a were prepared using methods similar to thosedescribed for the preparation of Example 356

TABLE 32a

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

TABLE 32b Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 32a. Example: Name ¹H NMR (400 MHz) δ ppm LCMS357: (R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(4- (DMSO-d6) δ 0.69 (br.s., 3 HRMS m/z isopropoxyphenyl)ethylamino)pyrimidin-4- H) 1.20 (d, J =6.02 Hz, 6 H) 387.2032 yl)oxazolidin-2-one 1.39 (d, J = 6.90 Hz, 3 H)(M + H)⁺; 4.33-4.46 (m, 2 H) 4.51 Rt-1.54 min (dt, J = 11.93, 5.87 Hz, 1H) 4.74 (br. s., 1 H) 4.94- 5.05 (m, 1 H) 6.80 (d, J = 8.41 Hz, 2 H)7.17-7.29 (m, 3 H) 8.12 (d, J = 5.67 Hz, 1 H) 358:(R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(4- The NMR not taken (not HRMSm/z isobutoxy-3-methylphenyl)ethylamino)pyrimidin-4- enough materialmade). 415.2340 yl)oxazolidin-2-one (M + H)⁺; Rt-1.98 min 359:(R)-3-(6-chloro-2-(((S)-1-(4- (DMSO-d6) δ 0.56 (d, HRMS m/z(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4- J = 6.11 Hz, 3 H)0.78-1.00 477.1054 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (m, 1 H)1.41 (d, J = 6.85 (M + H)⁺; Hz, 3 H) 3.78 (br. s., 1 H) Rt-2.39 min4.66-4.74 (m, 1 H) 4.97- 5.10 (m, 1 H) 7.16 (s, 1 H) 7.28 (d, J = 8.22Hz, 2 H) 7.47 (d, J = 8.66 Hz, 2 H) 8.40 (d, J = 7.63 Hz, 1 H) 360:(R)-3-(5-fluoro-2-(((S)-1-(4- (DMSO-d6) δ 0.49 (br. s., 3 HRMS m/z(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4- H) 1.43 (d, J = 7.04Hz, 3 H) 431.1345 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 4.39 (dd, J= 8.31, 4.30 Hz, (M + H)⁺; 1 H) 4.46-4.60 (m, 2 H) Rt-2.05 min 4.92 (br.s., 2 H) 7.23- 7.31 (m, 2 H) 7.47 (d, J = 8.61 Hz, 2 H) 7.98 (br. s., 1H) 8.34 (d, J = 2.20 Hz, 1 H) 361:(R)-3-(6-chloro-2-(((S)-1-(2-fluoro-4- (DMSO-d6) δ 0.50 (d, HRMS m/z(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4- J = 6.02 Hz, 3 H) 0.93(dd, 465.0958 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one J = 12.30, 6.33Hz, 1 H) 1.42 (M + H)⁺; (d, J = 6.99 Hz, 3 H) 4.25- Rt-2.45 min 4.57 (m,3 H) 4.66 (br. s., 1 H) 5.14-5.27 (m, 1 H) 7.13- 7.25 (m, 2 H) 7.29 (d,J = 10.07 Hz, 1 H) 7.40- 7.59 (m, 1 H) 8.36-8.49 (m, 1 H) 362:(R)-3-(5-fluoro-2-(((S)-1-(2-fluoro-4- (DMSO-d6) δ 0.48 (br. s., 3 HRMSm/z (trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4- H) 0.91-1.34 (m, 1H) 1.45 449.1243 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (d, J = 7.04Hz, 3 H) 4.34- (M + H)⁺; 4.59 (m, 3 H) 5.16 (br. s., 1 Rt-2.09 min H)7.20 (d, J = 8.51 Hz, 1 H) 7.32 (d, J = 10.51 Hz, 1 H) 7.52 (t, J = 8.56Hz, 1 H) 8.06 (br. s., 1 H) 8.37 (br. s., 1 H) 363:(R)-3-(5-fluoro-2-(((S)-1-(2-fluoro-4- (DMSO-d6) δ 0.40-0.82 HRMS m/zisobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)- (m, 3 H) 0.95 (d, J= 6.65 437.2005 1-hydroxyethyl)oxazolidin-2-one Hz, 6 H) 1.40 (d, J =6.99 (M + H)⁺; Hz, 3 H) 1.98 (dquin, Rt-2.28 min J = 13.29, 6.64, 6.64,6.64, 6.64 Hz, 1 H) 3.71 (d, J = 6.50 Hz, 2 H) 4.38-4.70 (m, 4 H) 5.12(br. s., 1 H) 6.65-6.78 (m, 2 H) 7.29 (t, J = 9.00 Hz, 1 H) 7.89 (br.s., 1 H) 8.35 (br. s., 1 H) 364: (R)-3-(2-(((S)-1-(4- (DMSO-d6) δ 0.62(br. s., 3 HRMS m/z (difluoromethoxy)phenyl)ethyl)amino)-5- H) 1.42 (d,J = 6.99 Hz, 3 H) 413.1433 fluoropyrimidin-4-yl)-4-((R)-1- 4.35-4.44 (m,1 H) 4.47- (M + H)⁺; hydroxyethyl)oxazolidin-2-one 4.54 (m, 1 H) 4.56(br. s., 1 Rt-1.83 min H) 4.91 (br. s., 1 H) 7.10 (d, J = 8.51 Hz, 2 H)6.95-7.35 (m, 1 H) 7.41 (d, J = 8.61 Hz, 2 H) 7.94 (br. s., 1 H) 8.34(d, J = 2.64 Hz, 1 H) 365: (R)-3-(5-fluoro-2-(((S)-1-(3-fluoro-4-(DMSO-d6) δ 0.26-1.06 HRMS m/z(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4- (m, 3 H) 1.44 (d, J =6.99 449.1244 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one Hz, 3 H)4.35-4.61 (m, 2 (M + H)⁺; H) 5.21 (br. s., 3 H) 7.25- Rt-2.09 min 7.38(m, 1 H) 7.42-7.55 (m, 2 H) 8.00 (br. s., 1 H) 8.37 (br. s., 1 H) 366:(R)-3-(6-chloro-2-(((S)-1-(4- (DMSO-d6) δ 0.65 (d, HRMS m/z(difluoromethoxy)phenyl)ethyl)amino)pyrimidin-4- J = 6.06 Hz, 3 H)0.87-1.02 429.1139 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (m, 1 H)1.42 (d, J = 6.70 (M + H)⁺; Hz, 3 H) 4.36-4.54 (m, 2 Rt-2.20 min H)4.69-4.79 (m, 1 H) 4.99- 5.11 (m, 1 H) 6.96-7.39 (m, 1 H) 7.12 (d, J =8.51 Hz, 2 H) 7.17 (d, J = 7.24 Hz, 1 H) 7.43 (d, J = 8.51 Hz, 2 H) 8.39(d, J = 8.02 Hz, 1 H) 367: (R)-3-(6-chloro-2-(((S)-1-(3-fluoro-4-(DMSO-d6) δ 0.57 (d, HRMS m/z(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4- J = 6.21 Hz, 3 H) 1.43(d, 465.0959 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one J = 6.75 Hz, 3H) 4.31-4.55 (M + H)⁺; (m, 3 H) 4.71 (br. s., 1 H) Rt-2.43 min 4.99-5.13(m, 1 H) 7.20 (s, 1 H) 7.30 (d, J = 8.56 Hz, 1 H) 7.40-7.58 (m, 2 H)8.41 (d, J = 7.19 Hz, 1 H) 368: (R)-3-(5-fluoro-2-(((S)-1-(4- (DMSO-d6)δ 0.48 (br. s., 3 HRMS m/z(isobutylsulfonyl)phenyl)ethyl)amino)pyrimidin-4- H) 0.96 (dd, J = 6.70,1.12 467.1758 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one Hz, 6 H) 1.46(d, J = 7.04 (M + H)⁺; Hz, 3 H) 2.00 (dquin, Rt-1.78 min J = 13.27,6.60, 6.60, 6.60, 6.60 Hz, 1 H) 3.15 (d, J = 6.46 Hz, 2 H) 4.34-4.61 (m,4 H) 4.98 (br. s., 1 H) 7.62 (d, J = 8.31 Hz, 2 H) 7.83 (d, J = 8.31 Hz,2 H) 8.07 (br. s., 1 H) 8.35 (br. s., 1 H) 369:(R)-3-(5-fluoro-2-(((S)-1-(4- (DMSO-d6) δ 0.45 (br. s., 3 HRMS m/z(isopropylsulfonyl)phenyl)ethyl)amino)pyrimidin-4- H) 1.11 (d, J = 6.80Hz, 6 H) 453.1604 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 1.43 (d, J= 7.04 Hz, 3 H) (M + H)⁺; 3.33 (dt, J = 13.58, 6.78 Hz, Rt-1.57 min 1 H)4.37 (dd, J = 8.05, 4.13 Hz, 1 H) 4.43-4.58 (m, 2 H) 4.97 (br. s., 1 H)7.61 (d, J = 8.36 Hz, 2 H) 7.76 (d, J = 8.36 Hz, 2 H) 8.06 (br. s., 1 H)8.33 (br. s., 1 H) 370: (R)-3-(6-chloro-2-(((S)-1-(4- (DMSO-d6) δ 0.53(d, HRMS m/z (isopropylsulfonyl)phenyl)ethyl)amino)pyrimidin-4- J = 6.21Hz, 3 H) 1.11 (dd, 469.1314 yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one J= 6.77, 3.74 Hz, 6 H) 1.43 (M + H)⁺; (d, J = 6.75 Hz, 3 H) 3.34 Rt-1.92min (dt, J = 13.17, 6.50 Hz, 1 H) 3.68 (br. s., 1 H) 4.38 (dd, J =16.43, 7.97 Hz, 2 H) 4.64- 4.76 (m, 1 H) 4.98-5.17 (m, 1 H) 7.18 (s, 1H) 7.62 (d, J = 8.31 Hz, 2 H) 7.78 (d, J = 8.27 Hz, 2 H) 8.50 (d, J =7.34 Hz, 1 H) 371: (R)-3-(2-(((S)-1-(4- (DMSO-d6) δ 0.24-0.35 HRMS m/z(cyclopropylmethoxy)phenyl)ethyl)amino)pyrimidin- (m, 2 H) 0.54 (dd, J =8.09, 399.2034 4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one 1.74 Hz, 2H) 0.74 (br. s., 3 (M + H)⁺; H) 1.12-1.24 (m, 1 H) 1.42 Rt-1.59 min (d,J = 6.99 Hz, 3 H) 3.76 (d, J = 6.99 Hz, 2 H) 4.36-4.50 (m, 3 H) 4.78 (d,J = 2.89 Hz, 1 H) 4.98-5.10 (m, 1 H) 6.84 (d, J = 8.61 Hz, 2 H)7.18-7.36 (m, 3 H) 8.15 (d, J = 5.62 Hz, 1 H) 372:(R)-3-(2-(((S)-1-(2-fluoro-4- (DMSO-d6) δ 0.51-0.82 HRMS m/zisobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)- (m, 3 H) 0.94 (d, J= 6.70 419.2102 1-hydroxyethyl)oxazolidin-2-one Hz, 6 H) 1.42 (d, J =6.85 (M + H)⁺; Hz, 3 H) 1.97 (dquin, Rt-1.95 min J = 13.32, 6.70, 6.70,6.70, 6.70 Hz, 1 H) 3.70 (d, J = 6.55 Hz, 2 H) 4.35-4.48 (m, 2 H)4.71-4.79 (m, 1 H) 5.24 (quin, J = 7.10 Hz, 1 H) 6.65-6.79 (m, 2 H)7.19- 7.34 (m, 2 H) 8.15 (br. s., 1 H)

Example 373:(R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one

To a microwave vial with stir bar was added(R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one(28 mg, 0.12 mmol) and DMSO (1 mL). To this reaction mixture was added(S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethanamine (48 mg, 0.17 mmol) andDIEA (61 ul, 0.35 mmol). Vial was capped and the reaction mixture washeated in a preheated sand bath at 80° C. for 18 hr. Reaction mixturewas purified by reverse phase HPLC. Product fractions combined, frozenand lyopholyzed to afford a TFA salt of(R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one(28 mg, 0.04 mmol, 38% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.01 (d, J=6.65Hz, 3H) 1.82 (d, J=7.04 Hz, 3H) 3.24 (s, 3H) 3.72-3.86 (m, 1H) 4.36-4.47(m, 1H) 4.60 (dd, J=9.39, 2.35 Hz, 1H) 4.92-5.01 (m, 1H) 5.48 (t, J=7.04Hz, 1H) 7.43 (d, J=8.61 Hz, 2H) 7.72 (s, 1H) 7.77-7.85 (m, 4H) 8.02 (d,J=7.04 Hz, 1H) 10.95 (d, J=6.65 Hz, 1H)). LCMS m/z 460.2 (M+H)⁺, Rt 0.82min. HRMS (B) m/z 460.1213 (M+H)⁺, Rt 2.28 min.

The compounds in Table 33a were prepared using methods similar to thosedescribed for the preparation of Example 373.

TABLE 33a

374*

375*

376

377

378

379 *Examples 374 and 375 were obtain in free form

TABLE 33b Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table33a. Example: Name 1H NMR (400 MHz, CDCl₃) δ ppmHRMS 374: (R)-3-(6-chloro-2- 0.89 (br. s., 3 H) 1.56 (br. s., 3 H) 3.20(br. HRMS (B) m/z (((S)-1-(2,5-difluoro-4-(1- s., 3 H) 3.96 (s, 3 H)4.28-4.37 (m, 1 H) 493.1567 methyl-1H-pyrazol-4- 4.50 (dd, J = 9.39,2.89 Hz, 1 H) 4.88 (ddd, (M + H)⁺; yl)phenyl)ethyl) J = 8.50, 4.32, 2.98Hz, 1 H) 5.30 (quin, Rt-2.35 min amino)pyrimidin-4-yl)-4- J = 6.97 Hz, 1H) 5.50 (br. s., 1 H) 7.07 (dd, ((R)-1-methoxyethyl) J = 10.91, 6.36 Hz,1 H) 7.21 (dd, J = 10.88, oxazolidin-2-one 6.04 Hz, 1 H) 7.55 (s, 1 H)7.76 (d, J = 2.45 Hz, 1 H) 7.79 (s, 1 H) 375: (R)-3-(6-chloro-2-0.69-0.95 (m, 3 H) 1.57-1.61 (m, 3 H) HRMS (B) m/z (((S)-1-(2-fluoro-4-3.16 (br. s., 3 H) 4.26-4.37 (m, 1 H) 4.49 463.1170 (trifluoromethyl)(dd, J = 9.39, 2.74 Hz, 1 H) 4.78-4.90 (m, 1 (M + H)⁺;phenyl)ethyl)amino)pyrim- H) 5.37 (quin, J = 6.93 Hz, 1 H) 5.51 (br. s.,Rt-2.74 min idin-4-yl)-4-((R)-1- 1 H) 7.33 (d, J = 9.44 Hz, 1 H)7.38-7.43 methoxyethyl)oxazolidin- (m, 1 H) 7.44-7.51 (m, 1 H) 7.56 (s,1 H) 2-one 376: (R)-3-(6-chloro-2- 1.01 (d, J = 4.21 Hz, 3 H) 1.72-1.77(m, 3 HRMS (B) m/z (((S)-1-(2-(4- H) 3.21 (br. s., 3 H) 4.31-4.42 (m, 1H) 494.0823 chlorophenyl)thiazol-5- 4.53 (dd, J = 9.46, 2.76 Hz, 1 H)4.89 (ddd, (M + H)⁺; yl)ethyl)amino)pyrimidin-4- J = 8.36, 4.21, 2.79Hz, 1 H) 5.46 (br. s., 1 Rt-2.80 min yl)-4-((R)-1- H) 7.42-7.48 (m, 2 H)7.65 (s, 1 H) 7.80 methoxyethyl)oxazolidin- (d, J = 8.56 Hz, 3 H) 2-one377: (R)-3-(2-(((S)-1-(5- 1.00 (d, J = 6.26 Hz, 3 H) 1.74 (d, J = 7.04HRMS (B) m/z (4-chlorophenyl) isoxazol- Hz, 3 H) 3.46 (s, 3 H) 4.03-4.19(m, 1 H) 444.1433 3-yl)ethyl)amino) 4.43 (t, J = 8.80 Hz, 1 H) 4.65 (dd,J = 9.59, (M + H)⁺; pyrimidin-4-yl)-4-((R)-1- 2.54 Hz, 1 H) 5.03 (ddd, J= 7.92, 4.60, 2.74 Rt-2.21 min methoxyethyl)oxazolidin- Hz, 1 H) 5.44(quin, J = 7.14 Hz, 1 H) 6.69 2-one (s, 1 H) 7.45 (d, J = 8.61 Hz, 2 H)7.71 (d, J = 8.61 Hz, 2 H) 7.80 (d, J = 7.04 Hz, 1 H) 7.94 (d, J = 7.04Hz, 1 H) 10.98 (d, J = 7.43 Hz, 1 H) 378: (R)-3-(2-(((S)-1-(1- 1.04 (d,J = 5.87 Hz, 3 H) 1.75 (d, J = 6.26 HRMS (B) m/z (4-chlorophenyl)-1H-Hz, 3 H) 3.31 (s, 3 H) 3.95 (br. s., 1 H) 443.1598 imidazol-4-yl)ethyl)4.46 (t, J = 8.61 Hz, 1 H) 4.60 (dd, J = 9.39, (M + H)⁺;amino)pyrimidin-4-yl)-4- 2.35 Hz, 1 H) 5.07 (d, J = 3.13 Hz, 1 H) 5.57Rt-1.57 min ((R)-1-methoxyethyl) (br. s., 1 H) 7.44 (d, J = 8.61 Hz, 2H) 7.57 oxazolidin-2-one (d, J = 8.22 Hz, 2 H) 7.61 (br. s., 1 H) 7.85(d, J = 7.04 Hz, 1 H) 7.96 (d, J = 6.65 Hz, 1 H) 8.53 (br. s., 1 H)10.90 (d, J = 6.65 Hz, 1 H) 379: (R)-3-(2-(((S)-1-(2,5- 0.97 (d, J =6.65 Hz, 3 H) 1.67 (d, J = 7.04 HRMS (B) m/z difluoro-4-(6- Hz, 3 H)2.88 (s, 3 H) 3.30 (s, 3 H) 3.67- 470.2007 methylpyridin-3- 3.89 (m, 1H) 4.37-4.49 (m, 1 H) 4.61 (dd, (M + H)⁺; yl)phenyl)ethyl)amino)pyrim- J= 9.39, 2.35 Hz, 1 H) 4.94-5.07 (m, 1 H) Rt-1.53 minidin-4-yl)-4-((R)-1- 5.62 (quin, J = 6.95 Hz, 1 H) 7.22-7.26 (m,methoxyethyl)oxazolidin- 1 H) 7.48 (dd, J = 10.37, 6.06 Hz, 1 H) 7.662-one (d, J = 8.22 Hz, 1 H) 7.82 (d, J = 7.04 Hz, 1 H) 7.97 (d, J = 7.04Hz, 1 H) 8.34 (d, J = 8.22 Hz, 1 H) 9.00 (s, 1 H) 11.04 (d, J = 7.83 Hz,1 H)

Example 380:(S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

Step 1

To a microwave vial with stir bar was added(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one(147 mg, 0.49 mmol) and DMSO (4 mL). To this reaction mixture was added(S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethanamine HCl (148 mg, 0.54 mmol)and DIEA (0.26 mL, 1.47 mmol). Vial capped and the reaction mixture washeated in a preheated sand bath at 110° C. for 42 hr. The reactionmixture was diluted with water and extracted with EtOAc. Organic phasescombined, washed with water, brine, dried (Na₂SO₄), filtered andconcentrated onto silica gel. Silica gel column chromatography(EtOAc/Heptane 0 to 100%) provided(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one(82 mg, 0.16 mmol, 33% yield). ¹H NMR (400 MHz, CDCl₃) δ 0.82 (br. s.,9H) 0.90-0.98 (m, 3H) 1.71 (d, J=6.90 Hz, 3H) 4.13 (q, J=7.16 Hz, 1H)4.21-4.32 (m, 1H) 4.42-4.51 (m, 1H) 4.56 (dd, J=8.31, 2.79 Hz, 1H) 5.39(br. s., 1H) 7.34-7.45 (m, 2H) 7.57 (d, J=5.77 Hz, 1H) 7.64 (s, 1H)7.76-7.86 (m, 2H) 8.22 (d, J=5.82 Hz, 1H). LCMS m/z 502.3 (M+H)⁺, Rt0.92 min.

Step 2

To a round bottom flask containing a stir bar and(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one(82 mg, 0.16 mmol) was added DCM (1 mL) followed by the addition of TFA(1 mL). Resulting reaction mixture allowed to stir 30 min at RT. Thevolatiles were then removed and the residue neutralized by the additionof a saturated solution of NaHCO₃. The aqueous mixture was thenextracted with DCM. Organic phases combined, washed with water, brine,dried (Na₂SO₄), filtered and concentrated to a brown foam of(R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one(61 mg, 0.14 mmol, 84% yield) which was used without furtherpurification. LCMS m/z 446.2 (M+H)⁺, Rt 0.71 min.

Step 3

To a round bottom flask with stir bar was added(R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one(19 mg, 0.04 mmol) followed by the addition of DCM (1 mL) undernitrogen. Mixture was cooled to 0° C. in a ice/water bath. To this coldsolution was added DIEA (0.03 mL, 0.17 mmol) followed by the addition ofmethanesulfonyl chloride (10 μL, 0.13 mmol). Reaction mixture stirredfor 1 hr at 0° C. The reaction mixture was then quenched with water anddiluted with DCM. Phases partitioned and the aqueous phase extractedwith DCM. Organic layers combined and washed with brine, dried (Na₂SO₄),filtered and concentrated to afford a orange residue of(S)-1-((R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-2-oxooxazolidin-4-yl)ethylmethanesulfonate (21 mg, 0.04 mmol, 94% yield). LCMS m/z 524.2 (M+H)⁺,Rt 0.75 min.

Step 4

To a microwave vial containing(S)-1-((R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-2-oxooxazolidin-4-yl)ethylmethanesulfonate (21 mg, 0.04 mmol) in DMF (1 mL) was added sodium azide(13 mg, 0.20 mmol). Resulting reaction mixture heated to 50° C. for 1 hrin a sand bath then to 80° C. for 42 hr. Reaction mixture was dilutedwith water and extracted with EtOAc. Organic phases combined, washedwith brine, dried (Na₂SO₄), filtered and concentrated to a yellowresidue of(S)-4-((R)-1-azidoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one(14 mg, 0.030 mmol, 74.2% yield). LCMS m/z 471.2 (M+H)⁺, Rt 0.92 min.

Step 5

To a round bottom flask containing(S)-4-((R)-1-azidoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one(14 mg, 0.03 mmol) and stir bar was added THF (1 mL) andtrimethylphosphine (0.06 mL, 0.06 mmol, 1.0 M in THF). The resultingreaction mixture allowed to stir 2 hr at RT. A second addition oftrimethylphosphine (0.06 mL, 0.06 mmol) occurred and the mixture allowedto stir 1.5 hr at RT. Reaction was quenched by the addition of asaturated solution of NH₄Cl and EtOAc. The phases were partitioned andaqueous phase extracted with EtOAc. Organic phases combined and washedwith brine, dried (Na₂SO₄), filtered and concentrated to a yellowresidue. Residue dissolved in DMSO and purified by reverse phase HPLC.Product fractions combined, frozen and lyopholyzed to afford(S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one(2.6 mg, 4.60 μmol, 15% yield) as a TFA salt. ¹H NMR (400 MHz, CD₃CN) δ1.26-1.44 (m, 3H) 1.68 (d, J=6.65 Hz, 3H) 3.83 (quin, J=6.26 Hz, 1H)4.43-4.53 (m, 1H) 7.46 (d, J=8.61 Hz, 2H) 7.76 (s, 1H) 7.89 (d, J=8.61Hz, 2H) 8.20 (br. s., 1H). LCMS m/z 445.2 (M+H)⁺, Rt 0.65 min. HRMS (B)m/z 445.1211 (M+H)⁺, Rt 1.58 min.

The compounds in Table 34a were prepared using methods similar to thosedescribed for the preparation of Example 380

TABLE 34a

381

382

383

TABLE 34b Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 34a. Example: Name 1H NMR (400 MHz) δ ppm HRMS381: (S)-4-((R)-1- (DMSO) 1.03-1.32 (m, 3 H) 1.55 (d, HRMS (B) m/zaminoethyl)-3-(2-(((S)-1- J = 6.65 Hz, 3 H) 3.86 (br. s., 1 H) 4.51 (d,428.1598 (1-(4-chlorophenyl)-1H- J = 7.04 Hz, 1 H) 5.23 (br. s., 1 H)7.28 (d, (M + H)⁺; imidazol-4-yl)ethyl) J = 5.87 Hz, 1 H) 7.60-7.68 (m,2 H) 7.73 Rt-1.12 min amino)pyrimidin-4- (d, J = 8.61 Hz, 2 H) 7.83 (br.s., 1 H) 8.25 yl)oxazolidin-2-one (d, J = 5.87 Hz, 1 H) 382:(S)-4-((R)-1- (DMSO) 1.09 (br. s., 3 H) 1.56 (d, J = 7.04 HRMS (B) m/zaminoethyl)-3-(2-(((S)-1- Hz, 3 H) 4.45-4.54 (m, 1 H) 5.37 (br. s., 1429.1438 (5-(4-chlorophenyl) H) 7.00 (s, 1 H) 7.26 (d, J = 5.87 Hz, 1 H)(M + H)⁺; isoxazol-3-yl)ethyl)amino) 7.60 (d, J = 8.61 Hz, 2 H) 7.87 (d,J = 8.61 Rt-1.49 min pyrimidin-4-yl)oxazolidin- Hz, 2 H) 8.07 (br. s., 1H) 8.24 (d, J = 5.87 2-one Hz, 1 H) 383: (S)-4-((R)-1- (CDCl₃) 1.24 (br.s., 1 H) 1.53 (d, J = 5.87 HRMS (B) m/z aminoethyl)-3-(2-(((S)-1- Hz, 3H) 2.64 (br. s., 3 H) 3.31 (br. s., 3 H) 455.2005 (2,5-difluoro-4-(6-4.42 (br. s., 1 H) 7.23-7.26 (m, 3 H) 7.40 (M + H)⁺; methylpyridin-3-(br. s., 1 H) 7.95-8.12 (m, 2 H) 8.67 (br. Rt-1.06 minyl)phenyl)ethyl)amino)pyrim- s., 1 H) idin-4-yl)oxazolidin-2-one

Example 384:(S)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(methylamino)ethyl)oxazolidin-2-one

To a microwave vial containing(S)-1-((R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-2-oxooxazolidin-4-yl)ethylmethanesulfonate (20 mg, 0.04 mmol) in DMF (1 mL) was added methyl amine(30 mg, 0.38 mmol, 40% wt in H₂O). Resulting reaction mixture allowed tostir at 80° C. for 18 hr whereupon a second addition of methylamine (0.1mL, 40% wt in H₂O) occurred. The reaction mixture was stirrred at 80° C.for 18 hr. The reaction mixture was then diluted with water andextracted with EtOAc. Organic phases combined and washed with brine,dried (Na₂SO₄), filtered and concentrated. Residue dissolved in DMSO andpurified by reverse phase HPLC. Product fractions combined, frozen andlyopholyzed to afford a TFA salt of(S)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-(methylamino)ethyl)oxazolidin-2-one(3.4 mg, 5.87 μmol, 15% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.47 (d,J=5.87 Hz, 3H) 1.78 (d, J=7.04 Hz, 3H) 2.70 (s, 3H) 4.02 (br. s., 1H)4.14 (br. s., 2H) 5.33 (br. s., 1H) 5.73 (d, J=6.26 Hz, 1H) 6.23 (d,J=5.48 Hz, 1H) 7.41 (d, J=8.61 Hz, 2H) 7.78 (s, 1H) 7.83 (d, J=8.22 Hz,2H) 8.05 (d, J=5.48 Hz, 1H). LCMS m/z 459.2 (M+H)⁺, Rt 0.73 min. HRMS(B) m/z 459.1373 (M+H)⁺, Rt 1.68 min.

Example 385:(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one

To a microwave vial with stir bar was added(R)-4-((R)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (20mg, 0.09 mmol) and DMSO (1 mL). To this reaction mixture was added(S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethanamine (34 mg, 0.13 mmol)and DIEA (46 uL, 0.26 mmol). Vial was then capped and heated in apreheated sand bath at 80° C. for 2 hr. Reaction mixture was thenpurified by reverse phase HPLC. Product fractions combined, frozen andlyopholyzed to afford a TFA salt of(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one(4.2 mg, 7.63 μmol, 8.74% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.21 (dd,J=24.26, 6.26 Hz, 3H) 1.74 (d, J=6.65 Hz, 3H) 4.52-4.58 (m, 2H)4.79-5.06 (m, 1H) 5.29 (br. s., 1H) 5.65 (t, J=6.85 Hz, 1H) 7.41 (d,J=8.61 Hz, 2H) 7.52 (s, 1H) 7.57 (d, J=9.00 Hz, 2H) 7.82 (d, J=6.65 Hz,1H) 7.98 (d, J=7.04 Hz, 1H) 8.48 (s, 1H) 10.97 (d, J=6.65 Hz, 1H)). LCMSm/z 431.1 (M+H)⁺, Rt 0.61 min. HRMS (B) m/z 431.1392 (M+H)⁺, Rt 1.54min.

The compounds in Table 35a were prepared using methods similar to thosedescribed for the preparation of Example 385.

TABLE 35a

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

TABLE 35b Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 35a. Example: Name 1H NMR (400 MHz, CDCl₃) δppm HRMS 386: (R)-3-(2-(((S)-1-(5- 10.84 (d, J = 6.7 Hz, 1 H), 8.02 (d,J = 7.0 Hz, HRMS (B) m/z (4-chlorophenyl) isoxazol- 1 H), 7.79 (d, J =7.0 Hz, 1 H), 7.71 (d, 432.1242 3-yl)ethyl)amino) J = 8.6 Hz, 2 H), 7.46(d, J = 8.2 Hz, 2 H), (M + H)⁺; pyrimidin-4-yl)-4-((R)-1- 6.63 (s, 1 H),5.33 (quin, J = 6.9 Hz, 1 H), Rt-2.18 min fluoroethyl)oxazolidin-2-4.95-5.21 (m, 2 H), 4.58-4.71 (m, 1 H), one 4.43-4.56 (m, 1 H), 1.75 (d,J = 7.0 Hz, 3 H), 1.17 (dd, J = 23.9, 5.9 Hz, 3 H) 387:(R)-3-(2-(((S)-1-(2- 1.18 (dd, J = 24.26, 6.65 Hz, 3 H) 1.82 (d, HRMS(B) m/z (4-chlorophenyl) thiazol-5- J = 7.04 Hz, 3 H) 4.44-4.55 (m, 1 H)4.57- 448.1014 yl)ethyl)amino) pyrimidin- 4.66 (m, 1 H) 4.69-4.94 (m, 1H) 5.00- (M + H)⁺; 4-yl)-4-((R)-1- 5.13 (m, 1 H) 5.40 (quin, J = 6.65Hz, 1 H) Rt-2.27 min fluoroethyl)oxazolidin-2- 7.43 (d, J = 8.22 Hz, 2H) 7.75 (s, 1 H) 7.77- one 7.88 (m, 3 H) 8.04 (d, J = 6.65 Hz, 1 H)11.00 (d, J = 5.48 Hz, 1 H) 388: (R)-3-(2-(((S)-1-(1- 1.36 (dd, J =23.87, 6.26 Hz, 3 H) 1.71 (d, HRMS (B) m/z (4-chlorophenyl)-1H- J = 6.26Hz, 3 H) 4.46-4.58 (m, 1 H) 4.59- 431.1400 imidazol-4-yl)ethyl) 4.69 (m,1 H) 4.86-5.12 (m, 2 H) 5.59 (br. (M + H)⁺; amino)pyrimidin-4-yl)-4- s.,1 H) 7.42 (d, J = 8.61 Hz, 2 H) 7.57 (d, Rt-1.55 min ((S)-1-fluoroethyl)J = 9.00 Hz, 3 H) 7.90 (d, J = 6.65 Hz, 1 H) oxazolidin-2-one 7.99 (d, J= 7.04 Hz, 1 H) 8.41 (br. s., 1 H) 11.02 (d, J = 7.04 Hz, 1 H) 389:(R)-3-(2-(((S)-1-(2- 1.26 (dd, J = 21.91, 6.65 Hz, 3 H) 1.81 (d, HRMS(B) m/z (4-chlorophenyl) thiazol-5- J = 7.04 Hz, 3 H) 4.43-4.55 (m, 1 H)4.57- 448.1007 yl)ethyl)amino) pyrimidin- 4.65 (m, 1 H) 4.65-4.93 (m, 2H) 5.33 (M + H)⁺; 4-yl)-4-((S)-1- (quin, J = 6.65 Hz, 1 H) 7.45 (d, J =8.22 Hz, Rt-2.22 min fluoroethyl)oxazolidin-2- 2 H) 7.71 (s, 1 H) 7.81(d, J = 8.61 Hz, 2 H) one 7.91 (d, J = 7.04 Hz, 1 H) 8.08 (d, J = 7.04Hz, 1 H) 10.94 (d, J = 5.87 Hz, 1 H) 390: (R)-3-(2-(((S)-1-(5- 1.48 (dd,J = 23.48, 6.26 Hz, 3 H) 1.73 (d, HRMS (B) m/z (4-chlorophenyl)isoxazol- J = 7.04 Hz, 3 H) 4.41-4.56 (m, 1 H) 4.67 432.12333-yl)ethyl)amino) (dd, J = 9.20, 2.54 Hz, 1 H) 4.74-5.05 (m, 2 (M + H)⁺;pyrimidin-4-yl)-4-((S)-1- H) 5.22 (t, J = 6.65 Hz, 1 H) 6.62 (s, 1 H)Rt-2.16 min fluoroethyl)oxazolidin-2- 7.46 (d, J = 8.22 Hz, 2 H) 7.70(d, J = 8.22 one Hz, 2 H) 7.86 (d, J = 7.04 Hz, 1 H) 7.99 (d, J = 7.04Hz, 1 H) 10.88 (d, J = 6.26 Hz, 1 H) 391: (R)-3-(2-(((S)-1-(3- 1.11 (dd,J = 24.26, 7.04 Hz, 3 H) 1.90 (d, HRMS (B) m/z (4-chlorophenyl)-1,2,4- J= 7.04 Hz, 3 H) 4.40-4.48 (m, 1 H) 4.50- 433.1190 oxadiazol-5- 4.57 (m,1 H) 4.66-4.89 (m, 1 H) 4.93- (M + H)⁺; yl)ethyl)amino)pyrimidin-4- 5.02(m, 1 H) 5.30-5.41 (m, 1 H) 7.47 (d, Rt-2.30 minyl)-4-((R)-1-fluoroethyl) J = 8.61 Hz, 2 H) 7.84 (d, J = 7.04 Hz, 1 H)oxazolidin-2-one 8.00 (d, J = 8.61 Hz, 2 H) 8.10 (d, J = 6.65 Hz, 1 H)11.06 (d, J = 4.30 Hz, 1 H) 392: (R)-4-((R)-1- 1.20 (dd, J = 23.87, 6.26Hz, 3 H) 1.84 (d, HRMS (B) m/z fluoroethyl)-3-(2-(((S)-1- J = 7.04 Hz, 3H) 4.46-4.55 (m, 1 H) 4.57- 483.1232 (2-(2-(trifluoromethyl) 4.65 (m, 1H) 4.68-4.93 (m, 1 H) 5.07 (d, (M + H)⁺; pyridin-4-yl)thiazol-5- J =5.87 Hz, 1 H) 5.46 (t, J = 6.85 Hz, 1 H) Rt-2.06 minyl)ethyl)amino)pyrimidin-4- 7.80 (d, J = 7.04 Hz, 1 H) 7.86 (s, 1 H)7.94 yl)oxazolidin-2-one (d, J = 5.09 Hz, 1 H) 8.04 (d, J = 7.04 Hz, 1H) 8.17 (s, 1 H) 8.83 (d, J = 5.09 Hz, 1 H) 11.14 (br. s., 1 H) 393:(R)-4-((R)-1- 1.20 (dd, J = 23.87, 6.26 Hz, 3 H) 1.84 (d, HRMS (B) m/zfluoroethyl)-3-(2-(((S)-1- J = 7.04 Hz, 3 H) 4.44-4.56 (m, 1 H) 4.57-483.1233 (2-(6-(trifluoromethyl) 4.65 (m, 1 H) 4.68-4.94 (m, 1 H) 5.07(d, (M + H)⁺; pyridin-3-yl)thiazol-5- J = 5.48 Hz, 1 H) 5.45 (t, J =6.65 Hz, 1 H) Rt-2.07 min yl)ethyl)amino)pyrimidin-4- 7.72-7.88 (m, 3 H)8.03 (d, J = 7.04 Hz, 1 yl)oxazolidin-2-one H) 8.36 (d, J = 7.83 Hz, 1H) 9.21 (s, 1 H) 11.12 (br. s., 1 H) 394: (R)-3-(2-(((S)-1-(1- 1.21 (dd,J = 23.48, 6.65 Hz, 3 H) 1.69 (d, HRMS (B) m/z (4-chlorophenyl)-1H- J =6.65 Hz, 3 H) 4.48-4.56 (m, 1 H) 4.59- 431.1407pyrazol-4-yl)ethyl)amino) 4.64 (m, 1 H) 4.87-5.25 (m, 3 H) 7.43 (d, (M +H)⁺; pyrimidin-4-yl)-4-((R)-1- J = 8.61 Hz, 2 H) 7.62 (d, J = 8.61 Hz, 2H) Rt-1.95 min fluoroethyl)oxazolidin-2- 7.67 (s, 1 H) 7.74 (d, J = 6.65Hz, 1 H) 7.95- one 8.02 (m, 2 H) 10.74 (d, J = 5.48 Hz, 1 H) 395:(R)-3-(2-(((S)-1-(2- 1.17 (dd, J = 23.48, 4.70 Hz, 3 H) 1.76 (d, HRMS(B) m/z (4-chlorophenyl) thiazol-5- J = 6.65 Hz, 3 H) 4.39 (dd, J =9.39, 4.30 Hz, 466.0916 yl)ethyl)amino)-5- 1 H) 4.60 (t, J = 9.00 Hz, 1H) 4.68-4.90 (M + H)⁺; fluoropyrimidin-4-yl)-4- (m, 2 H) 5.32 (d, J =5.09 Hz, 1 H) 7.44 (d, Rt-2.32 min ((R)-1-fluoroethyl) J = 8.61 Hz, 2 H)7.79 (d, J = 8.61 Hz, 2 H) oxazolidin-2-one 7.85 (s, 1 H) 8.19 (d, J =3.13 Hz, 1 H) 396: (R)-3-(2-(((S)-1-(1- 1.28 (dd, J = 23.09, 6.65 Hz, 3H) 1.68 (d, HRMS (B) m/z (4-chlorophenyl)-1H- J = 6.65 Hz, 3 H)4.44-4.55 (m, 1 H) 4.57- 431.1407 pyrazol-4-yl)ethyl)amino) 4.65 (m, 1H) 4.67-4.78 (m, 1 H) 4.81- (M + H)⁺; pyrimidin-4-yl)-4-((S)-1- 5.04 (m,1 H) 5.09 (t, J = 6.65 Hz, 1 H) 7.43 Rt-1.88 minfluoroethyl)oxazolidin-2- (d, J = 8.61 Hz, 2 H) 7.56-7.67 (m, 3 H) one7.84 (d, J = 6.65 Hz, 1 H) 7.93 (s, 1 H) 8.00 (d, J = 7.04 Hz, 1 H)10.73 (d, J = 5.87 Hz, 1 H) 397: (R)-3-(2-(((S)-1-(1- 1.24 (dd, J =23.87, 5.87 Hz, 3 H) 1.68 (d, HRMS (B) m/z (4-chlorophenyl)-1H- J = 6.65Hz, 3 H) 4.39 (dd, J = 9.39, 3.91 Hz, 449.1303pyrazol-4-yl)ethyl)amino)- 1 H) 4.62 (t, J = 9.00 Hz, 1 H) 4.76-4.99(M + H)⁺; 5-fluoropyrimidin-4-yl)-4- (m, 2 H) 5.14 (q, J = 7.04 Hz, 1 H)7.43 (d, Rt-2.20 min ((R)-1-fluoroethyl) J = 8.61 Hz, 2 H) 7.57 (d, J =8.61 Hz, 2 H) oxazolidin-2-one 7.76 (s, 1 H) 7.96 (s, 1 H) 8.15 (d, J =3.91 Hz, 1H) 398: (R)-3-(2-(((S)-1-(5- 1.15 (dd, J = 24.26, 6.26 Hz, 3H) 1.72 (d, HRMS (B) m/z (4-chlorophenyl) isoxazol- J = 7.04 Hz, 3 H)4.42 (dd, J = 9.39, 4.30 Hz, 450.1145 3-yl)ethyl)amino)-5- 1 H) 4.62 (t,J = 9.00 Hz, 1 H) 4.73-5.07 (M + H)⁺; fluoropyrimidin-4-yl)-4- (m, 2 H)5.17-5.23 (m, 1 H) 6.54 (s, 1 H) Rt-2.26 min ((R)-1-fluoroethyl) 7.45(d, J = 8.61 Hz, 2 H) 7.68 (d, J = 8.22 oxazolidin-2-one Hz, 2 H) 8.15(d, J = 3.52 Hz, 1 H) 399: (R)-3-(2-(((S)-1-(1- 1.29 (dd, J = 23.87,5.09 Hz, 3 H) 1.75 (d, HRMS (B) m/z (4-chlorophenyl)-1H- J = 6.65 Hz, 3H) 4.38 (d, J = 6.26 Hz, 1 H) 449.1313 imidazol-4-yl)ethyl) 4.58 (t, J =8.80 Hz, 1 H) 4.93 (br. s., 1 H) (M + H)⁺; amino)-5-fluoropyrimidin-5.32 (br. s., 1 H) 7.42 (d, J = 7.83 Hz, 3 H) Rt-1.52 min4-yl)-4-((R)-1-fluoroethyl) 7.56 (d, J = 7.83 Hz, 2 H) 8.19 (br. s., 1H) oxazolidin-2-one 8.62 (br. s., 1 H) 400: (R)-3-(2-(((S)-1-(1-1.33-1.53 (m, 3 H) 1.71 (br. s., 3 H) 2.60 HRMS (B) m/z(4-chlorophenyl)-2-methyl- (s, 3 H) 4.54 (br. s., 1 H) 4.62 (d, J = 7.04445.1556 1H-imidazol-4- Hz, 1 H) 4.94-5.20 (m, 1 H) 5.69 (br. s., 1 (M +H)⁺; yl)ethyl)amino)pyrimidin-4- H) 7.30 (d, J = 8.22 Hz, 2 H) 7.59 (d,J = 8.61 Rt-1.42 min yl)-4-((S)-1-fluoroethyl) Hz, 2 H) 7.82-8.02 (m, 1H) oxazolidin-2-one 401: (R)-4-((S)-1- 1.36 (dd, J = 24.26, 5.87 Hz, 3H) 1.72 (d, HRMS (B) m/z fluoroethyl)-3-(2-(((S)-1- J = 5.87 Hz, 3 H)4.44-4.58 (m, 1 H) 4.63 415.1695 (1-(4-fluorophenyl)-1H- (dd, J = 9.19,2.93 Hz, 1 H) 4.87-5.18 (m, 2 (M + H)⁺; imidazol-4-yl)ethyl) H) 5.54(br. s., 1 H) 7.39-7.58 (m, 3 H) Rt-1.34 min amino)pyrimidin-4- 7.87 (d,J = 6.65 Hz, 1 H) 7.97 (d, J = 5.87 yl)oxazolidin-2-one Hz, 1 H) 8.26(br. s., 1 H) 10.95 (br. s., 1 H) 402: (R)-3-(2-(((S)-1-(2,5- 1.32 (dd,J = 23.09, 6.26 Hz, 3 H) 1.66 (d, HRMS (B) m/z difluoro-4-(4-methyl-1H-J = 7.04 Hz, 3 H) 2.45 (s, 3 H) 4.45-4.56 447.1761 imidazol-1- (m, 1 H)4.63 (dd, J = 9.00, 2.74 Hz, 1 H) (M + H)⁺; yl)phenyl)ethyl)amino)pyrim-4.70-4.97 (m, 2 H) 5.48 (quin, J = 6.95 Hz, Rt-1.20 minidin-4-yl)-4-((S)-1- 1 H) 7.11 (s, 1 H) 7.56 (dd, J = 10.17, 6.65fluoroethyl)oxazolidin-2- Hz, 1 H) 7.86 (d, J = 7.04 Hz, 1 H) 8.00 (d,one J = 7.04 Hz, 1 H) 8.59 (s, 1 H) 11.07 (br. s., 1 H)

Example 403:(R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

A solution of(R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (10mg, 0.044 mmol),(S)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)ethanamine(19 mg, 0.065 mmol, 1.5 equiv), and N-ethyl-N-isopropylpropan-2-amine(0.031 mL, 0.175 mmol, 4 equiv) in DMSO (0.5 mL) was heated at 90° C.for 3 hours. The reaction was then cooled to room temperature.Purification by reverse phase HPLC provided the trifluoroacetate salt of(R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one(14 mg, white solid) in 55% yield. ¹H NMR (400 MHz, CDCl₃) δ 10.83 (d,J=7.1 Hz, 1H), 9.06 (d, J=2.3 Hz, 1H), 8.15 (dd, J=8.5, 2.4 Hz, 1H),7.93-8.04 (m, 2H), 7.81 (dd, J=7.7, 6.3 Hz, 2H), 6.61 (d, J=2.6 Hz, 1H),5.28 (quin, J=7.1 Hz, 1H), 4.96-5.17 (m, 1H), 4.68-4.81 (m, 1H), 4.62(dd, J=9.1, 3.2 Hz, 1H), 4.45-4.54 (m, 1H), 1.72 (d, J=7.1 Hz, 3H),1.14-1.29 (m, 3H); HRMS m/z 466.1625 (M+H)⁺; Rt-1.83 min.

The compounds in Table 36a were prepared using methods similar to thosedescribed for the preparation of Example 403.

TABLE 36a

404

405

406

TABLE 36b Chemical name, NMR chemical shifts and LCMS signal for eachcompound listed in Table 36a. Example: Name ¹H NMR (400 MHz, CDCl₃) δppm LCMS 404: (R)-3-(2-(((S)-1-(1-(4- 8.22 (d, J = 5.5 Hz, 1H), 7.77 (s,1H), 7.45 LCMS m/z chlorophenyl)-1H-imidazol-4- (m, 3H), 7.30 (d, J =8.7 Hz, 2H), 7.11 (s, 417.1 yl)ethyl)amino)pyrimidin-4-yl)- 1H), 5.14(m, 1H), 4.93 (m, 1H), 4.48 (m, (M + H)⁺;4-(fluoromethyl)oxazolidin-2-one 4H), 1.63 (d, J = 6.8 Hz, 3H) Rt-0.59min. 405: (R)-3-(2-(((S)-1-(5-(4- 8.25 (m, 1H), 7.68 (m, 2H), 7.53 (m,1H), LCMS m/z chlorophenyl)isoxazol-3-yl)eth- 7.44 (m, 2H), 6.48 (s,1H), 5.47 (m, 1H), 418.2 yl)amino)pyrimidin-4-yl)-4- 4.95 (m, 1H), 4.50(m, 4H), 1.66 (d, J = 6.8 (M + H)⁺; (fluoromethyl)oxazolidin-2-one Hz,3H) Rt-0.82 min. 406: (R)-3-(2-(((S)-1-(1-(4- 7.96 (m, 1H), 7.82 (m,1H), 7.60 (d, J = 8.4 LCMS m/z chlorophenyl)-2-methyl- Hz, 2H), 7.30 (d,J = 8.4 Hz, 2H), 7.22 (s, 445.2 1H-imidazol-4- 1H), 5.73 (m, 1H), 5.42(m, 1H), 5.05- (M + H)⁺; yl)ethyl)amino)pyrimidin-4- 4.90 (m, 1H), 4.54(m, 2H), 2.60 (s, 3H), Rt-0.67 min. yl)-4-((R)-1-fluoroeth- 1.72 (d, J =6.7 Hz, 3H), 1.34-1.20 (m, 3H) yl)oxazolidin-2-one

Example 407(R)-4-((S)-1-hydroxyethyl)-3-(2-(((S)-1-(1-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

Example 407 was prepared using a method similar to that described forthe preparation of Example 28. Product was purified by reverse phaseHPLC. ¹H NMR (400 MHz, CD₂Cl₂) δ 8.23 (d, J=4.18 Hz, 1H), 8.19 (d,J=4.88 Hz, 1H), 7.37 (d, J=4.88 Hz, 1H), 6.68 (br, s, 1H), 6.68-6.63 (m,1H), 5.03 (br, s, 1H), 4.80 (br, s, 1H), 4.50-4.36 (m, 3H), 4.09-3.91(m, 3H), 2.90-2.79 (m, 2H), 1.99-1.79 (m, 2H), 1.78-1.65 (m, 2H), 1.59(s, 6H), 1.52-1.32 (m, 2H), 1.23 (d, J=6.97 Hz, 3H), 1.18 (d, J=6.27 Hz,3H), HRMS(C) tR=3.62 min; MS m/z 523.2649 (M+H)+

Example 408 (R)-3-(2-(((S)-1-(1-(4-chloro-3-(trifluoromethoxy)phenyl)piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one

Example 408 was prepared using a method similar to that described forthe preparation of Example 28. TFA salt form of product was converted tofree base form by using a PL-HCO3 MP SPE cartridge, eluting with MeOH.¹H NMR (400 MHz, CD₂Cl₂) δ 8.07 (d, J=5.33 Hz, 1H), 7.25 (d, J=4.33 Hz,1H), 7.19 (d, J=9.48 Hz, 1H), 6.76-6.68 (m, 2H), 4.98 (br, s, 1H), 4.69(br, s, 1H), 4.39-4.25 (m, 3H), 3.90 (br, s, 1H), 3.65-3.56 (m, 2H),2.68-2.56 (m, 2H), 1.86-1.15 (m, 6H), 1.12 (d, J=6.52 Hz, 3H), 1.07 (d,J=4.74 Hz, 3H), HRMS(C) tR=4.44 min; MS m/z 530.1782 (M+H)+

Example 409(S)-3-(2-(((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one

A mixture of(S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one(40 mg, 0.135 mmol), (S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethanaminehydrochloride (61.1 mg, 0.271 mmol), Huenig's base (0.095 mL, 0.541mmol) in DMSO (0.7 mL) under argon atmosphere was heated at 107° C. for˜16 hr. The mixture was diluted with DMSO and water, filtered through asyringe filter and purified by reverse phase HPLC. Selected fractionswere collected and lyophilized providing(S)-3-(2-(((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-oneas its trifluoroacetic acid salt (35.4 mg).

¹H NMR (400 Mhz, CD₃OD) δ ppm 8.26 (br. s., 1H), 7.42-7.54 (m, 1H),7.23-7.33 (m, 2H), 6.55-6.91 (m, 1H), 5.26 (q, J=6.9 Hz, 1H), 4.52 (t,J=9.0 Hz, 1H), 4.36-4.45 (m, 1H), 1.53 (d, J=7.0 Hz, 4H), 0.78 (br. s.,3H). HRMS m/z 449.1412 (M+H)+; Rt-2.27 min.

Examples 410 and 411(S)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one/(S)-3-(2-(((R)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one

A mixture of(S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(40 mg, 0.153 mmol),(S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine/(R)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine(mixture of diastereomers ˜3/1, 37.7 mg, 0.168 mmol) and Huenig's base(0.059 mL, 0.337 mmol) in DMSO (0.7 mmol) under argon atmosphere washeated/radiated in the microwave at 140° C. for 15 min. The mixture wasdiluted with DMSO and water, filtered through a syringe filter andpurified by reverse phase HPLC. Selected fractions were collected andlyophilized providing(S)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one(31.8 mg; first eluted product) and(S)-3-(2-(((R)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one(11.5 mg; second eluted product) as their trifluoroacetic acid salts.

410: First eluted product: ¹H NMR (500 Mhz, CD₃OD) δ ppm 8.22 (s, 1H),8.03-7.93 (m, 2H), 7.54-7.46 (m, 3H), 5.84 (m, 1H), 5.49 (q, J=7.2 Hz,1H), 5.13 (dt, J=8.4, 3.1 Hz, 1H), 4.60-4.21 (m, 2H), 2.74 (m, 1H), 1.75(d, J=7.2 Hz, 3H), 0.90 (br. s, 3H). HRMS m/z 465.1260 (M+H)+; Rt-2.41min.

411: Second eluted product: ¹H NMR (500 Mhz, CD₃OD) δ ppm 8.19 (dd,J=7.5, 6.0 Hz, 1H), 8.10-7.91 (m, 2H), 7.55-7.50 (m, 2H), 7.47 (d, J=5.8Hz, 1H), 6.08 (td, J=55.6, 3.5 Hz, 1H), 5.40 (t, J=7.1 Hz, 1H),4.59-4.42 (m, 1H), 4.39 (s, 1H), 3.03 (s, 1H), 1.72 (d, J=7.2 Hz, 3H),1.03 (d, J=7.2 Hz, 3H). HRMS m/z 465.1250 (M+H)+; Rt-2.42 min.

The following Examples were prepared using a method similar to thatdescribed for the preparation of Examples 410/411

Example 412(S)-3-(2-(((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one

¹H NMR (400 Mhz, CD₃OD) δ ppm 8.19 (d, J=6.7 Hz, 1H), 7.70 (d, J=6.7 Hz,1H), 7.47-7.56 (m, 1H), 7.28-7.40 (m, 2H), 6.60-6.95 (m, 1H), 5.57-5.95(m, 1H), 5.47 (m, J=5.1 Hz, 1H), 5.12 (dt, J=7.8, 3.13 Hz, 1H),4.46-4.60 (m, 2H), 1.63 (d, J=7.0 Hz, 3H), 0.77-0.95 (m, 3H). HRMS m/z431.1506 (M+H)+; Rt-2.09 min.

Example 413 and 414(S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one/(S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-(((R)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

A mixture of(S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one30 mg, 0.115 mmol),1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethanamine (53.1 mg, 0.230mmol), Huenig's Base 0.05 mL, 0.287 mmol) in DMSO (0.7 mL) under argonatmosphere was heated at 120° C. for ˜16 hr. Additional amine (2 eq) wasadded and heating was continued for 3 hrs. More amine (2 eq) was addedand heating was continued for 3 hr. The mixture was diluted with DMSOand water, filtered through a syringe filter and purified by reversephase HPLC. Selected fractions were collected and lyophilized providing(S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one/(S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-(((R)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-oneas their trifluoroacetic acid salts as off-white solids.

413: First eluted product (2.8 mg): ¹H NMR (500 Mhz, CD₃OD) δ ppm 8.98(s, 2H), 8.16 (s, 1H), 7.59 (dd, J=7.3, 2.3 Hz, 1H), 7.56-7.45 (m, 2H),7.18 (t, J=9.0 Hz, 1H), 6.40-5.96 (m, 1H), 5.25 (q, J=6.9 Hz, 1H), 4.52(dd, J=9.4, 2.8 Hz, 1H), 4.42 (t, J=8.4 Hz, 1H), 3.08 (s, 1H), 2.34 (d,J=2.0 Hz, 3H), 1.62 (d, J=7.0 Hz, 3H), 1.05 (d, J=7.2 Hz, 3H). HRMS m/z473.1916 (M+H)+; Rt-2.12 min.

414: Second eluted product (2.9 mg): ¹H NMR (500 Mhz, CD₃OD) δ ppm 8.96(s, 2H), 8.16 (s, 1H), 7.57 (dd, J=7.5, 2.4 Hz, 1H), 7.53-7.43 (m, 2H),7.17 (t, J=9.0 Hz, 1H), 5.92 (t, J=56.9 Hz, 1H), 5.30 (q, J=7.0 Hz, 1H),5.13 (dt, J=6.9, 3.3 Hz, 1H), 4.57-4.40 (m, 2H), 2.53 (s, 1H), 2.34 (d,J=2.0 Hz, 3H), 1.64 (d, J=7.0 Hz, 3H), 0.87 (s, 3H). HRMS m/z 473.1919(M+H)+; Rt-2.17 min.

The compounds in Table 37a were prepared using methods similar to thosedescribed for the preparation of Examples 35, 36, or 37/38.

TABLE 37a

415

416

417

418

419

420

421

422 and 423

TABLE 37b Chemical name, NMR chemical shifts, chiral separationconditions and LCMS signal for compounds listed in Table 37a. Chiralseparation conditions, peak identification and Example: Name analyticaldata 415: (R)-4-((R)-1-hydroxyethyl)- Chiral separation was achieved bychiral SFC column 3-(2-(((S)-1-(3-(1-methyl-1H- chromatography (ColumnOD-H 21 × 250 mm 30% MeOH + indol-6-yl)-1,2,4-oxadiazol-5- 20 mM NH4OHin CO₂, flow 80 g/min, 238 nm UV yl)ethyl)amino)pyrimidin-4- collection)to give (R)-4-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3- yl)oxazolidin-2-one(1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(1-methyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4- yl)oxazolidin-2-one415: Peak 2: (11 mg): (CDCl₃) δ 8.25 (d, J = 5.7 Hz, 1H), 8.08 (d, J =1.1 Hz, 1H), 7.80 (dd, J = 8.3, 1.4 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H),7.54 (d, J = 5.7 Hz, 1H), 7.19 (d, J = 3.1 Hz, 1H), 6.54 (dd, J = 3.0,0.9 Hz, 1H), 5.96 (s, 1H), 5.35 (s, 1H), 4.96-4.81 (m, 1H), 4.55 (dd, J= 9.5, 2.5 Hz, 1H), 4.38 (dd, J = 9.3, 8.4 Hz, 1H), 3.88 (s, 4H), 3.19(s, 1H), 2.63 (s, 8H), 1.80 (d, J = 6.7 Hz, 1H), 0.96 (d, J = 6.4 Hz,3H). HRMS(B) m/z 449.1812RT = 2.18 min. 416: (R)-4-((R)-1-hydroxyethyl)-Chiral separation was achieved by chiral SFC column 3-(2-(((S)-1-(3-(3-chromatography (Column IA-H 21 × 250 mm 15% MeOH in(trifluoromethoxy)phenyl)-1,2,4- CO₂, flow 80 g/min, 238 nm UVcollection) to give (R)-4- oxadiazol-5-((R)-1-hydroxyethyl)-3-(2-(((R)-1-(3-(3- yl)ethyl)amino)pyrimidin-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5- yl)oxazolidin-2-oneyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one 416: Peak 2 (62 mg):(CDCl₃) δ 8.25 (d, J = 5.8 Hz, 1H), 8.02 (dt, J = 7.7, 1.3 Hz, 1H), 7.95(dt, J = 2.3, 1.3 Hz, 1H), 7.67-7.46 (m, 2H), 7.40 (ddt, J = 8.3, 2.5,1.1 Hz, 1H), 5.90 (s, 1H), 5.40 (s, 1H), 4.86 (ddd, J = 8.4, 4.7, 2.5Hz, 1H), 4.55 (dd, J = 9.5, 2.5 Hz, 1H), 4.41 (t, J = 8.9 Hz, 1H), 3.90(s, 1H), 3.52 (s, 1H), 2.77 (s, 1H), 1.86-1.77 (m, 3H), 1.34-1.19 (m,1H), 1.03 (s, 3H). HRMS(B) m/z 480.1369. RT = 2.67 min. Chiral RT = 4.80min 417: (R)-3-(2-(((S)-1-(3-(1,2- Chiral separation was achieved bychiral SFC column dimethyl-1H-indol-4-yl)-1,2,4- chromatography (ColumnIA 21 × 250 mm 40% MeOH in oxadiazol-5- CO₂, flow 75 g/min, 238 nm UVcollection) to give (R)-3-(2- yl)ethyl)amino)pyrimidin-4-yl)-4-(((R)-1-(3-(1,2-dimethyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(1,2-dimethyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one.417: Peak 2 (120 mg): (CDCl₃) δ 8.16 (d, J = 6.2 Hz, 1H), 7.89 (dd, J =7.5, 0.9 Hz, 1H), 7.63 (d, J = 6.2 Hz, 1H), 7.45 (dt, J = 8.1, 1.0 Hz,1H), 7.34-7.21 (m, 1H), 6.95-6.85 (m, 1H), 5.47-5.19 (m, 1H), 1.91-1.79(m, 3H), 4.81 (ddd, J = 8.3, 4.3, 2.4 Hz, 1H), 4.52 (dd, J = 9.5, 2.4Hz, 1H), 4.35 (dd, J = 9.5, 8.3 Hz, 1H), 3.75 (s, 4H), 3.52 (s, 2H),2.51 (d, J = 1.0 Hz, 3H), 0.86 (d, J = 5.5 Hz, 3H). HRMS(B) m/z463.1968. RT = 2.23 min. Chiral RT = 3.35 min 418:(R)-3-(2-(((S)-1-(3-(4- Chiral separation was achieved by chiral SFCcolumn chloro-3- chromatography (Column AD-H 21 × 250 mm 15% MeOH +(trifluoromethoxy)phenyl)-1,2,4- 10 mM NH4OH in CO₂, flow 75 g/min, 238nm UV oxadiazol-5- collection) to give (R)-3-(2-(((R)-1-(3-(4-chloro-3-yl)ethyl)amino)pyrimidin-4-yl)-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-chloro-3-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one418: Peak 2 (120 mg): CDCl₃) δ 8.25 (d, J = 5.8 Hz, 1H), 8.05 (p, J =1.4 Hz, 1H), 7.98 (dd, J = 8.4, 1.9 Hz, 1H), 7.70- 7.49 (m, 2H), 5.74(s, 1H), 5.51-5.35 (m, 1H), 4.85 (ddd, J = 8.3, 4.8, 2.5 Hz, 1H), 4.54(dd, J = 9.3, 2.5 Hz, 1H), 4.41 (dd, J = 9.4, 8.3 Hz, 1H), 2.72 (s, 1H),1.79 (d, J = 7.1 Hz, 3H), 1.63 (d, J = 7.1 Hz, 2H), 1.05 (s, 3H).HRMS(B) m/z 515.1243. Chiral RT = 4.20 min 419: (R)-3-(2-(((S)-1-(3-(4-Chiral separation was achieved by chiral SFC columnchloro-3-methylphenyl)-1,2,4- chromatography (Column IA 21 × 250 mm 30%MeOH in oxadiazol-5- CO₂, flow 75 g/min, 238 nm UV collection) to give(R)-3-(2- yl)ethyl)amino)pyrimidin-4-yl)-4-(((R)-1-(3-(4-chloro-3-methylphenyl)-1,2,4-oxadiazol-5-((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-chloro-3-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one419: Peak 2 (92 mg) (CDCl₃) δ 8.20 (d, J = 6.0 Hz, 1H), 7.95 (d, J = 2.1Hz, 1H), 7.83 (dd, J = 8.3, 2.2 Hz, 1H), 7.61 (d, J = 6.0 Hz, 1H), 7.47(d, J = 8.3 Hz, 1H), 5.33 (d, J = 7.1 Hz, 1H), 4.84 (ddd, J = 8.4, 4.7,2.4 Hz, 1H), 1.89-1.74 (m, 3H), 4.56 (dd, J = 9.4, 2.5 Hz, 1H), 4.41(dd, J = 9.4, 8.3 Hz, 1H), 3.74 (d, J = 41.0 Hz, 1H), 3.52 (s, 1H), 2.46(s, 3H), 1.12-0.85 (m, 3H). HRMS(B) m/z 411.1365. Chiral RT = 2.85 min420: (R)-3-(2-(((S)-1-(3-(4- Chiral separation was achieved by chiralSFC column bromo-3-methoxyphenyl)-1,2,4- chromatography (Column IA 21 ×250 mm 30% MeOH in oxadiazol-5- CO₂, flow 90 g/min, 238 nm UVcollection) to give (R)-3-(2- yl)ethyl)amino)pyrimidin-4-yl)-4-(((R)-1-(3-(4-bromo-3-methoxyphenyl)-1,2,4-oxadiazol-5-((R)-1-hydroxyethyl)oxazolidin- yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-2-one hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(4-bromo-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one420: Peak 2 (96 mg) (CDCl₃) δ 8.22 (d, J = 6.0 Hz, 1H), 7.67 (d, J = 8.1Hz, 1H), 7.63-7.52 (m, 3H), 5.37 (s, 1H), 4.84 (ddd, J = 8.3, 4.7, 2.4Hz, 1H), 1.91-1.72 (m, 3H), 4.55 (dd, J = 9.5, 2.5 Hz, 1H), 4.41 (t, J =8.9 Hz, 1H), 4.00 (s, 3H), 3.52 (s, 1H), 1.02 (s, 3H). HRMS(B) m/z504.0757. Chiral RT = 3.50 min 421: (R)-3-(2-(((S)-1-(3-(3-(tert- Chiralseparation was achieved by chiral SFC columnbutyl)phenyl)-1,2,4-oxadiazol-5- chromatography (Column IA-H 21 × 250 mm15% MeOH in yl)ethyl)amino)pyrimidin-4-yl)-4- CO₂, flow 80 g/min, 238 nmUV collection) to give (R)-3-(2- ((R)-1-hydroxyethyl)oxazolidin-(((R)-1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5- 2-oneyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-oneand (R)-3-(2-(((S)-1-(3-(3- (tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one421: Peak 2 (62 mg): (CDCl₃) δ 8.25 (d, J = 5.7 Hz, 1H), 8.08 (t, J =1.8 Hz, 1H), 7.87 (dt, J = 7.6, 1.4 Hz, 1H), 7.66- 7.51 (m, 1H), 7.43(t, J = 7.8 Hz, 1H), 5.92-5.68 (m, 1H), 5.35 (d, J = 9.3 Hz, 1H), 4.86(ddd, J = 8.4, 4.4, 2.4 Hz, 1H), 1.74-1.64 (m, 1H), 4.55 (dd, J = 9.5,2.5 Hz, 1H), 4.39 (dd, J = 9.4, 8.3 Hz, 1H), 3.51 (d, J = 5.3 Hz, 3H),3.00 (d, J = 4.9 Hz, 1H), 1.79 (d, J = 7.2 Hz, 3H), 1.38 (s, 9H), 1.08(q, J = 5.5 Hz, 1H), 1.00 (s, 3H). HRMS(B) m/z 452.2172. RT = 2.88 min.Chiral RT = 5.20 min 422 and 423: (R)-3-(2-(((R)-1- Chiral separationwas achieved by chiral SFC column (3-(2,3-dihydro-1H-inden-5-yl)-chromatography (Column ID 21 × 250 mm 40% IPA + 10 mM 1,2,4-oxadiazol-5-NH4OH in CO₂, flow 75 g/min, 222 nm UV collection) toyl)ethyl)amino)pyrimidin-4-yl)-4- give(R)-3-(2-(((R)-1-(3-(2,3-dihydro-1H-inden-5-yl)-1,2,4-((R)-1-hydroxyethyl)oxazolidin-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 2-onehydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(2,3-dihydro-1H-inden-5-yl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- hydroxyethyl)oxazolidin-2-one422: First eluted product (15 mg): ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J= 5.8 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.81 (dd, J = 7.8, 1.7 Hz, 1H),7.50 (d, J = 5.7 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 5.81 (s, 1H), 5.27(d, J = 43.6 Hz, 1H), 4.70 (d, J = 7.9 Hz, 1H), 4.49 (dd, J = 9.3, 2.4Hz, 1H), 4.42- 4.09 (m, 2H), 3.51 (d, J = 3.1 Hz, 3H), 3.23 (s, 1H),2.98 (t, J = 7.4 Hz, 4H), 2.14 (p, J = 7.5 Hz, 2H), 1.78 (d, J = 7.0 Hz,3H), 1.75-1.62 (m, 0H), 1.21 (dd, J = 14.9, 6.3 Hz, 4H), 1.14 (d, J =5.5 Hz, 1H). HRMS(D) m/z 437.1944 (M + H). RT = 3.57 min. Chiral RT =2.35 min. 423: Second eluted product (63 mg): ¹H NMR (400 MHz, CDCl₃) δ8.25 (d, J = 5.7 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.83 (dd, J = 7.8,1.6 Hz, 1H), 7.54 (d, J = 5.7 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 5.79(s, 1H), 5.32 (s, 1H), 4.85 (ddd, J = 8.4, 4.5, 2.5 Hz, 1H), 4.55 (dd, J= 9.5, 2.5 Hz, 1H), 4.39 (t, J = 8.9 Hz, 1H), 3.75 (d, J = 49.5 Hz, 1H),3.51 (s, 1H), 2.97 (t, J = 7.4 Hz, 5H), 2.13 (p, J = 7.5 Hz, 2H), 1.78(d, J = 7.2 Hz, 3H), 1.63 (s, 1H), 1.23 (d, J = 6.1 Hz, 1H), 0.98 (d, J= 7.1 Hz, 4H). HRMS(D) m/z 437.1942 (M + H). RT = 3.58 min. Chiral RT =3.50 min.

Example 424 and 425(4R)-3-(2-((1-(5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

A solution of(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(150 mg, 0.529 mmol),1-[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamine (118 mg, 0.529mmol, 1.0 equiv), and DIEA (0.185 mL, 1.059 mmol, 2.0 equiv) in DMSO (2mL) was heated at 110° C. for 120 min. The reaction mixture was dilutedwith EtOAc (20 mL) and washed with water (10 mL), 4% brine (10 mL),concentrated in vacuo. The crude material,(R)-5-((R)-1-tert-Butoxy-ethyl)-1-(2-{1-[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-pyrimidin-4-yl)-imidazolidin-2-one,was carried to the next step without further purification.

(R)-5-((R)-1-tert-Butoxy-ethyl)-1-(2-{1-[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylamino}-pyrimidin-4-yl)-imidazolidin-2-one(200 mg, 0.411 mmol) was treated with 10:1 TFA/water (10 ml) for 2hours. The reaction was conc. in vacuo and neutralized by passingthrough a column of MP-carbonate eluting with MeOH/DCM/MeOH and Flashcolumn (silica, 15μ, 40 g) eluting w/ 5-60% EtOAc/heptane over 2.5 hoursto give(R)-3-(2-(((R)-1-(5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-oneand(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one

424: first eluted product (45 mg, 50.8%). HRMS m/z 430.1156.

425: Second eluted product (46 mg, 52.0%). ¹H NMR (400 MHz, CDCl3) δ8.67 (s, 1H), 8.09 (dq, J=8.4, 2.0, 1.6 Hz, 3H), 7.64 (d, J=6.4 Hz, 1H),7.58-7.48 (m, 2H), 5.48-5.27 (m, 1H), 4.94 (t, J=6.6 Hz, 1H), 4.63-4.40(m, 2H), 1.13 (d, J=6.5 Hz, 3H), 0.89 (d, J=7.1 Hz, 0H), 1.83-1.72 (m,3H). HRMS m/z 430.1156.

Example 426(S)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one

A mixture of(S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(23.35 mg, 0.089 mmol),(S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethanamine hydrochloride (30mg, 0.116 mmol) and Huenig's base (0.047 mL, 0.268 mmol) in DMSO (0.6mL) under argon atmosphere was heated at 80° C. for ˜16 hr. The mixturewas diluted with DMSO and water, filtered through a syringe filter andpurified by reverse phase HPLC. Selected fractions were collected andlyophilized providing(S)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-oneas its trifluoroacetic acid salt (30.2 mg) as a white solid.

¹H NMR (400 Mhz, CD₃OD) δ ppm 9.07 (br. s., 1H), 8.24 (d, J=6.3 Hz, 1H),7.85 (s, 1H), 7.53-7.72 (m, 5H), 5.64-6.06 (m, 1H), 5.36 (q, J=6.9 Hz,1H), 5.07-5.23 (m, 1H), 4.41-4.62 (m, 2H), 2.62-2.90 (m, 1H), 1.71 (d,J=6.7 Hz, 3H), 0.97 (d, J=7.0 Hz, 3H); LCMS m/z 463.2 (M+H)⁺, Rt 0.64min.

The following Example was prepared using a method similar to thatdescribed for the preparation of Example 426.

Example 427(S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-(((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

¹H NMR (400 Mhz, CD₃OD) δ ppm 9.13 (s, 1H), 8.25 (d, J=6.7 Hz, 1H), 7.86(s, 1H), 7.61-7.73 (m, 3H), 7.36 (m, J=8.6, 8.6 Hz, 2H), 5.69-6.06 (m,1H), 5.37 (q, J=6.7 Hz, 1H), 5.10-5.18 (m, 1H), 4.46-4.59 (m, 2H),2.67-2.82 (m, 1H), 1.72 (d, J=7.0 Hz, 3H), 0.98 (d, J=7.4 Hz, 3H) LCMSm/z 447.2 (M+H)⁺, Rt 0.57 min.

The Examples in Table 38a were prepared using methods similar to thosedescribed for the preparation of Examples 385 and 403.

TABLE 38a

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

TABLE 38b Chemical name, NMR chemical shifts, chiral separationconditions and LCMS signal for compounds listed in Table 38a. Example:Name ¹H NMR (400 MHz) δ ppm LCMS 428:(R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1- (CDCl₃) 11.13 (d, J = 5.9 Hz, 1H), LCMS (B) (2-(2-(trifluoromethyl)pyridin-4-yl)thiazol-5- 8.84 (d, J =5.0 Hz, 1 H), 8.17 (s, 1 m/z 483.1;yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2- H), 8.06 (d, J = 7.0 Hz, 1H), 7.89-7.96 Rt = 0.79 min. one (m, 2 H), 7.80 (s, 1 H), 5.34-5.44 (m,1 H), 4.81-4.90 (m, 1 H), 4.66-4.78 (m, 2 H), 4.59-4.65 (m, 1 H),4.47-4.55 (m, 1 H), 1.83 (d, J = 7.0 Hz, 3H), 1.21-1.32 (m, 3 H) 429:(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)- (CDCl₃) 8.22 (d, J = 2.9 Hz, 1 H),LCMS (B) 1H-imidazol-4-yl)ethyl)amino)-5- 7.75 (d, J = 1.2 Hz, 1 H),7.44 (d, m/z 435.1; fluoropyrimidin-4-yl)-4- J = 8.9 Hz, 2 H), 7.30 (d,J = 8.9 Hz, Rt = 0.62 min. (fluoromethyl)oxazolidin-2-one 2 H), 7.11 (s,1H), 5.57 (d, J = 7.7 Hz, 1 H), 5.02-5.14 (m, 1 H), 4.75-4.89 (m, 1 H),4.56-4.64 (m, 2 H), 4.43-4.53 (m, 2 H), 1.61 (d, J = 6.8 Hz, 3 H) 430:(R)-3-(5-fluoro-2-(((S)-1-(1-(4- (CDCl₃) 8.62 (d, J = 3.9 Hz, 1 H), LCMS(B) fluorophenyl)-1H-imidazol-4- 8.14-8.21 (m, 1 H), 7.48 (dd, m/z419.2; yl)ethyl)amino)pyrimidin-4-yl)-4- J = 8.9, 4.4 Hz, 3 H),7.24-7.34 (m, Rt = 0.57 min. (fluoromethyl)oxazolidin-2-one 2 H), 5.38(br. s., 1 H), 4.88-5.03 (m, 1 H), 4.42-4.73 (m, 4 H), 1.75 (t, J = 6.3Hz, 3 H) 431: (R)-3-(2-(((S)-1-(1-(3,4- (CDCl₃) 8.63 (br. s., 1 H), 8.17(d, LCMS (B) difluorophenyl)-1H-imidazol-4- J = 3.3 Hz, 1 H), 7.36-7.52(m, 4 m/z 437.2; yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4- H), 5.36(br. s., 1 H), 4.94 (d, Rt = 0.59 min. (fluoromethyl)oxazolidin-2-one J= 18.7 Hz, 1 H), 4.43-4.74 (m, 4 H), 1.74 (d, J = 7.1 Hz, 3 H) 432:(R)-3-(2-(((S)-1-(1-(4-chloro-3- (CDCl₃) 8.57 (s, 1 H), 8.18 (d, LCMS(B) fluorophenyl)-1H-imidazol-4- J = 1.9 Hz, 1 H), 7.63 (t, J = 7.6 Hz,1 m/z 453.1; yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4- H), 7.48 (br.s., 1 H), 7.35 (d, J = 8.5 Rt = 0.64 min. (fluoromethyl)oxazolidin-2-oneHz, 1 H), 7.24-7.29 (m, 1 H), 5.33 (d, J = 5.3 Hz, 1 H), 4.84-4.98 (m, 1H), 4.54-4.74 (m, 3 H), 4.48 (t, J = 7.5 Hz, 1 H), 1.73 (d, J = 6.5 Hz,3 H) 433: (R)-3-(2-(((S)-1-(1-(3-chloro-4- (CDCl₃) 8.56 (s, 1 H), 8.18(d, LCMS (B) fluorophenyl)-1H-imidazol-4- J = 1.9 Hz, 1H), 7.57-7.63 (m,1 m/z 453.1; yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4- H), 7.33-7.48(m, 3 H), 5.34 (br. Rt = 0.64 min. (fluoromethyl)oxazolidin-2-one s., 1H), 4.85-5.00 (m, 1 H), 4.41-4.75 (m, 4 H), 1.73 (d, J = 7.0 Hz, 3 H)434: (R)-3-(2-(((S)-1-(1-(4- (CDCl₃) 8.67 (s, 1 H), 8.17 (d, LCMS (B)(difluoromethyl)phenyl)-1H-imidazol-4- J = 3.3 Hz, 1 H), 7.76 (d, J =8.3 Hz, m/z 451.2; yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4- 2 H), 7.60(d, J = 8.4 Hz, 2 H), 7.51-7.57 Rt = 0.61 min.(fluoromethyl)oxazolidin-2-one (m, 1H), 6.58-6.90 (m, 1 H), 5.38 (d, J =6.5 Hz, 1 H), 4.86-5.01 (m, 1 H), 4.41-4.75 (m, 4H), 1.75 (d, J = 7.1Hz, 3 H) 435: (R)-3-(2-(((S)-1-(1-(4- (CDCl₃) 8.60 (d, J = 1.1 Hz, 1 H),LCMS (B) (difluoromethyl)-3-fluorophenyl)-1H- 8.17 (d, J = 3.3 Hz, 1 H),7.84 (t, m/z 469.2; imidazol-4-yl)ethyl)amino)-5- J = 7.8 Hz, 1 H), 7.53(d, J = 4.0 Hz, Rt = 0.63 min. fluoropyrimidin-4-yl)-4- 1 H), 7.41 (d,(fluoromethyl)oxazolidin-2-one J = 8.3 Hz, 1 H), 7.35 (d, J = 9.7 Hz, 1H), 6.78-7.10 (m, 1 H), 5.33 (d, J = 6.4 Hz, 1 H), 4.85-4.99 (m, 1 H),4.42-4.73 (m, 4 H), 1.73 (d, J = 7.1 Hz, 3 H) 436:(R)-3-(2-(((S)-1-(1-(3,5- (CDCl₃) 8.63 (s, 1 H), 8.16 (dd, LCMS (B)difluorophenyl)-1H-imidazol-4- J = 3.3, 2.0 Hz, 1 H), 7.51 (br. s., 1m/z 437.1; yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4- H), 7.09 (d, J =6.6 Hz, 2 H), 6.97-7.05 Rt = 0.59 min. (fluoromethyl)oxazolidin-2-one(m, 1 H), 5.35 (d, J = 6.4 Hz, 1 H), 4.40-4.93 (m, 5 H), 1.73 (d, J =7.0 Hz, 3 H) 437: (R)-3-(2-(((S)-1-(5-(4- (CDCl₃) 8.13 (d, J = 3.9 Hz, 1H), LCMS (B) chlorophenyl)isoxazol-3-yl)ethyl)amino)-5- 7.69 (d, J = 8.4Hz, 2 H), 7.46 (d, m/z 436.1; fluoropyrimidin-4-yl)-4- J = 8.4 Hz, 2 H),6.57 (s, 1 H), 5.18 Rt = 0.91 min. (fluoromethyl)oxazolidin-2-one (d, J= 7.1 Hz, 1 H), 4.93-5.08 (m, 1 H), 4.64-4.72 (m, 1 H), 4.55 (dd, J =8.7, 7.2 Hz, 1 H), 4.27-4.52 (m, 2 H), 1.71 (d, J = 7.1 Hz, 3 H) 438:(R)-3-(2-(((S)-1-(2-(4- (CDCl₃) 8.18 (d, J = 3.5 Hz, 1 H), LCMS (B)chlorophenyl)thiazol-5-yl)ethyl)amino)-5- 7.89 (s, 1 H), 7.75-7.80 (m, 2H), m/z 452.1; fluoropyrimidin-4-yl)-4- 7.44-7.50 (m, 2 H), 5.28 (d, J =6.6 Rt = 0.93 min. (fluoromethyl)oxazolidin-2-one Hz, 1 H), 4.80-4.93(m, 1 H), 4.68 (t, J = 8.9 Hz, 1 H), 4.42-4.49 (m, 1 H), 4.16-4.41 (m, 2H), 1.77 (d, J = 7.0 Hz, 3 H) 439: (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-(CDCl₃) 8.13 (d, J = 3.1 Hz, 1 H), LCMS (B)2-methyl-1H-imidazol-4-yl)ethyl)amino)-5- 7.58-7.63 (m, 2 H), 7.31-7.37m/z 449.2; fluoropyrimidin-4-yl)-4- (m, 2 H), 7.14-7.18 (m, 1 H), 5.41Rt = 0.65 min. (fluoromethyl)oxazolidin-2-one (br. s., 1 H), 4.77-4.96(m, 1 H), 4.46-4.72 (m, 4 H), 2.60 (s, 3 H), 1.70 (d, J = 6.9 Hz, 3 H)440: (R)-3-(5-fluoro-2-(((S)-1-(2-(2- (CDCl₃) 8.85 (d, J = 5.1 Hz, 1 H),LCMS (B) (trifluoromethyl)pyridin-4-yl)thiazol-5- 8.20 (d, J = 3.5 Hz, 1H), 8.16 (s, 1 m/z 487.1; yl)ethyl)amino)pyrimidin-4-yl)-4- H),7.92-7.96 (m, 1 H), 7.90 (s, 1 Rt = 0.86 min.(fluoromethyl)oxazolidin-2-one H), 5.36 (d, J = 7.0 Hz, 1 H), 4.78-4.91(m, 1 H), 4.24-4.72 (m, 4 H), 1.79 (d, J = 6.9 Hz, 3 H) 441:(R)-3-(2-(((S)-1-(2,5-difluoro-4-(2- (CDCl₃) 8.88 (d, J = 6.0 Hz, 1 H),LCMS (B) methylpyridin-4-yl)phenyl)ethyl)amino)-5- 8.19 (d, J = 3.0 Hz,1 H), 7.76 (d, m/z 462.2; fluoropyrimidin-4-yl)-4- J = 6.2 Hz, 1 H),7.72 (s, 1 H), 7.21-7.33 Rt = 0.60 min. (fluoromethyl)oxazolidin-2-one(m, 2 H), 5.19-5.30 (m, 1 H), 4.78 (br. s., 1 H), 4.64 (t, J = 8.8 Hz, 1H), 4.41-4.49 (m, 1 H), 4.09-4.37 (m, 2 H), 2.90 (s, 3 H), 1.63 (d, J =6.9 Hz, 3 H) 442: (R)-3-(2-(((S)-1-(2,5-difluoro-4-(6- (CDCl₃) 9.01 (s,1 H), 8.33 (d, LCMS (B) methylpyridin-3-yl)phenyl)ethyl)amino)-5- J =8.2 Hz, 1 H), 8.17 (d, J = 3.2 Hz, m/z 462.1; fluoropyrimidin-4-yl)-4- 1H), 7.67 (d, J = 8.3 Hz, 1 H), 7.21-7.29 Rt = 0.61 min.(fluoromethyl)oxazolidin-2-one (m, 2 H), 5.18-5.29 (m, 1 H), 4.06-4.83(m, 5 H), 2.89 (s, 3 H), 1.62 (d, J = 7.0 Hz, 3 H) 443:(R)-3-(2-(((S)-1-(2,5-difluoro-4-(6- (CDCl₃) 8.89 (s, 1 H), 8.15 (dd,LCMS (B) (trifluoromethyl)pyridin-3- J = 3.7, 1.2 Hz, 1 H), 8.06 (d, J =8.2 m/z 516.1; yl)phenyl)ethyl)amino)-5-fluoropyrimidin-4- Hz, 1 H),7.82 (d, J = 8.2 Hz, 1 H), Rt = 0.97 min.yl)-4-(fluoromethyl)oxazolidin-2-one 7.17-7.30 (m, 2 H), 5.28 (d, J =5.7 Hz, 1 H), 4.77-4.90 (m, 1 H), 4.67 (t, J = 8.8 Hz, 1 H), 4.49 (t, J= 7.8 Hz, 1 H), 4.07-4.29 (m, 2 H), 1.66 (d, J = 6.7 Hz, 3 H) 444:(R)-3-(2-(((S)-1-(2,5-difluoro-4-(2- (CDCl₃) 8.85 (d, J = 5.0 Hz, 1 H),LCMS (B) (trifluoromethyl)pyridin-4- 8.15 (dd, J = 3.4, 2.4 Hz, 1 H),7.84 m/z 516.0; yl)phenyl)ethyl)amino)-5-fluoropyrimidin-4- (s, 1 H),7.67 (d, J = 4.9 Hz, 1 H), Rt = 0.96 min.yl)-4-(fluoromethyl)oxazolidin-2-one 7.21-7.33 (m, 2 H), 5.28 (br. s., 1H), 4.81 (d, J = 14.6 Hz, 1 H), 4.67 (t, J = 8.8 Hz, 1 H), 4.45-4.53 (m,1 H), 4.07-4.33 (m, 2 H), 1.63-1.68 (m, 3 H) 445:(R)-3-(2-(((S)-1-(2,5-difluoro-4-(4- (CDCl₃) 8.82 (s, 1 H), 8.18 (d,LCMS (B) methyl-1H-imidazol-1- J = 3.1 Hz, 1 H), 7.39 (dd, J = 10.3, m/z451.1; yl)phenyl)ethyl)amino)-5-fluoropyrimidin-4- 6.0 Hz, 1 H),7.27-7.30 (m, 1 H), Rt = 0.58 min. yl)-4-(fluoromethyl)oxazolidin-2-one7.11 (s, 1 H), 5.19-5.28 (m, 1 H), 4.74 (br. s., 1 H), 4.64 (t, J = 8.6Hz, 1 H), 4.39-4.47 (m, 1 H), 4.13-4.32 (m, 2 H), 2.49 (s, 3 H), 1.63(d, J = 7.0 Hz, 3 H) 446: (R)-3-(2-(((S)-1-(1-(4- (CDCl₃) 8.72 (s, 1 H),8.18 (d, LCMS m/z (difluoromethyl)-3-fluorophenyl)-1H- J = 3.1 Hz, 1 H),7.79-7.91 (m, 1 483.0 (M + H)⁺, imidazol-4-yl)ethyl)amino)-5- H), 7.61(br. s., 1 H), 7.33-7.48 Rt 0.68 min; fluoropyrimidin-4-yl)-4-((S)-1-(m, 2 H), 6.94 (t, J = 54.0 Hz, 1 H), HPLC 2.801 min.fluoroethyl)oxazolidin-2-one 5.34 (d, J = 6.7 Hz, 1 H), 4.71-5.05 (m, 2H), 4.55-4.65 (m, 1 H), 4.50 (dd, J = 8.4, 6.5 Hz, 1 H), 1.74 (d, J =7.0 Hz, 3 H), 1.33 (dd, J = 23.5, 6.7 Hz, 3 H) 447:(R)-3-(2-(((S)-1-(1-(4- (CDCl₃) 8.81 (s, 1 H), 8.18 (d, LCMS m/z(difluoromethyl)phenyl)-1H-imidazol-4- J = 3.1 Hz, 1 H), 7.76 (d, J =8.2 Hz, 465.0 (M + H)⁺, yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4- 2 H),7.62 (d, J = 8.2 Hz, 2 H), 6.74 Rt 0.65 min;((S)-1-fluoroethyl)oxazolidin-2-one (t, J = 56.0 Hz, 1 H), 5.38 (q, J =6.7 HPLC 2.624 min. Hz, 1 H), 4.73-5.06 (m, 2 H), 4.59 (t, J = 8.8 Hz, 1H), 4.45-4.53 (m, 1 H), 1.76 (d, J = 7.0 Hz, 3 H), 1.34 (dd, J = 23.5,6.3 Hz, 3 H). 448: (R)-3-(2-(((S)-1-(1-(4-chloro-3- (CDCl₃) 8.73 (s, 1H), 8.18 (d, LCMS m/z fluorophenyl)-1H-imidazol-4- J = 3.1 Hz, 1 H),7.64 (t, J = 8.0 Hz, 1 467.0 (M + H)⁺,yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4- H), 7.57 (br. s., 1 H),7.29-7.44 Rt 0.69 min; ((S)-1-fluoroethyl)oxazolidin-2-one (m, 2 H),5.34 (d, J = 6.7 Hz, 1 H), HPLC 2.847 min. 4.73-4.87 (m, 1 H), 4.59 (t,J = 8.8 Hz, 1 H), 4.45-4.53 (m, 1 H), 1.74 (d, J = 7.0 Hz, 3 H), 1.33(dd, J = 23.1, 6.3 Hz, 3 H) 449: (R)-3-(2-(((S)-1-(1-(3,5- (CDCl₃) 8.58(s, 1 H), 8.18 (d, LCMS m/z difluorophenyl)-1H-imidazol-4- J = 2.7 Hz, 1H), 7.53 (br. s., 1 H), 451.1 (M + H)⁺,yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4- 7.09 (d, J = 5.1 Hz, 2 H),7.00 (t, Rt 0.64 min; ((S)-1-fluoroethyl)oxazolidin-2-one J = 8.4 Hz, 1H), 5.29-5.36 (m, 1 HPLC 2.132 min. H), 5.00 (br. s., 1 H), 4.87 (br.s., 1 H), 4.70-4.83 (m, 1 H), 4.54-4.64 (m, 1 H), 4.46-4.53 (m, 1 H),1.73 (d, J = 7.0 Hz, 3 H), 1.33 (dd, J = 23.1, 6.3 Hz, 3 H). 450:(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)- (CDCl₃) 8.64 (s, 1 H), 8.18 (d,LCMS m/z 1H-imidazol-4-yl)ethyl)amino)-5- J = 3.1 Hz, 1 H), 7.57 (d, J =8.6 Hz, 449.0 (M + H)⁺, fluoropyrimidin-4-yl)-4-((S)-1- 2 H), 7.51 (br.s., 1 H), 7.44 (d, Rt 0.67 min; fluoroethyl)oxazolidin-2-one J = 8.6 Hz,2 H), 5.35 (d, J = 6.7 Hz, HPLC 2.354 min. 1 H), 5.01 (br. s., 1 H),4.89 (br. s., 1 H), 4.71-4.86 (m, 1 H), 4.54-4.64 (m, 1 H), 4.44-4.53(m, 1 H), 1.74 (d, J = 7.0 Hz, 3 H), 1.33 (dd, J = 23.5, 6.7 Hz, 3 H).451: (R)-3-(5-fluoro-2-(((S)-1-(1-(4- (CDCl₃) 8.61 (s, 1 H), 8.18 (d,LCMS m/z fluorophenyl)-1H-imidazol-4- J = 2.7 Hz, 1 H), 7.48 (dd, J =8.4, 433.1 (M + H)⁺, yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- 4.1 Hz, 3H), 7.28-7.34 (m, 2 H), Rt 0.61 min; fluoroethyl)oxazolidin-2-one 5.35(d, J = 6.7 Hz, 1 H), 4.70-4.85 HPLC 1.997 min. (m, 1 H), 4.54-4.62 (m,1 H), 4.45-4.53 (m, 1 H), 1.75 (d, J = 7.0 Hz, 3 H), 1.33 (dd, J = 23.1,6.3 Hz, 3 H). 452: (R)-3-(2-(((S)-1-(5-(4- (CDCl₃) 8.11 (d, J = 3.5 Hz,1 H), LCMS m/z chlorophenyl)isoxazol-3-yl)ethyl)amino)-5- 7.69 (d, J =8.6 Hz, 2 H), 7.46 (d, 450.0 (M + H)⁺, fluoropyrimidin-4-yl)-4-((S)-1- J= 8.6 Hz, 2 H), 6.54 (s, 1 H), 5.17 Rt 0.96 min;fluoroethyl)oxazolidin-2-one (d, J = 5.1 Hz, 1 HPLC 4.131 min. H),4.69-4.92 (m, 2 H), 4.51-4.65 (m, 2 H), 1.70 (d, J = 7.0 Hz, 3 H), 1.30(dd, J = 23.1, 6.3 Hz, 3 H). 453: (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-(CDCl₃) 8.14 (d, J = 3.5 Hz, 1 H), LCMS m/z1H-pyrazol-4-yl)ethyl)amino)-5- 7.94 (s, 1 H), 7.68 (s, 1 H), 7.59 (d,449.0 (M + H)⁺, fluoropyrimidin-4-yl)-4-((S)-1- J = 8.6 Hz, 2 H), 7.43(d, J = 8.6 Hz, Rt 0.92 min; fluoroethyl)oxazolidin-2-one 2 H), 5.08 (q,J = 6.7 Hz, 1 H), 4.65-4.87 HPLC 3.864 min. (m, 2 H), 4.59 (t, J = 8.8Hz, 1 H), 4.47-4.55 (m, 1 H), 1.66 (d, J = 7.0 Hz, 3 H), 1.22 (dd, J =23.5, 6.7 Hz, 3 H). 454: (R)-3-(2-(((S)-1-(1-(3,5- (CDCl₃) 10.92 (d, J =6.7 Hz, 1 H), LCMS m/z difluorophenyl)-1H-imidazol-4- 8.30 (br. s., 1H), 7.99 (d, J = 6.7 433.2 (M + H)⁺,yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- Hz, 1 H), 7.88 (d, J = 7.0 Hz,1 H), Rt 0.59 min; fluoroethyl)oxazolidin-2-one 7.57 (br. s., 1 H),6.92-7.11 (m, 3 HPLC 1.946 min. H), 5.48 (d, J = 6.3 Hz, 1 H), 4.84-5.14(m, 2 H), 4.59-4.70 (m, 1 H), 4.48-4.57 (m, 1 H), 1.69 (d, J = 6.7 Hz, 3H), 1.34 (dd, J = 23.5, 5.9 Hz, 3 H). 455: (R)-3-(2-(((S)-1-(1-(4-(CDCl₃) 10.91 (d, J = 7.0 Hz, 1 H), LCMS m/z(difluoromethyl)-3-fluorophenyl)-1H- 8.24 (br. s., 1 H), 7.98 (d, J =6.7 465.2 (M + H)⁺, imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)- Hz, 1 H),7.88 (d, J = 7.0 Hz, 1 H), Rt 0.63 min;4-((S)-1-fluoroethyl)oxazolidin-2-one 7.82 (t, J = 7.4 Hz, 1 H), 7.58(br. s., HPLC 2.191 min. 1 H), 7.30-7.43 (m, 2 H), 6.94 (dt, J = 55.6,1.0 Hz, 1 H), 5.44 (br. s., 1 H), 4.80-5.22 (m, 2 H), 4.64 (d, J = 9.0Hz, 1 H), 4.54 (t, J = 8.8 Hz, 1 H), 1.71 (d, J = 6.3 Hz, 3 H), 1.36(dd, J = 23.5, 6.3 Hz, 3 H). 456: (R)-3-(2-(((S)-1-(1-(4- (CDCl₃) 11.00(d, J = 7.0 Hz, 1 H), LCMS m/z (difluoromethyl)phenyl)-1H-imidazol-4-8.46 (s, 1 H), 7.99 (d, J = 7.0 Hz, 1 447.3 (M + H)⁺,yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- H), 7.90 (d, J = 7.0 Hz, 1 H),7.75 Rt 0.58 min; fluoroethyl)oxazolidin-2-one (d, J = 8.2 Hz, 2 H),7.66 (s, 1 H), HPLC 1.898 min. 7.59 (d, J = 8.2 Hz, 2 H), 6.74 (t, J =55.6 Hz, 1 H), 5.58 (t, J = 6.8 Hz, 1 H), 4.91-5.14 (m, 2 H), 4.60-4.68(m, 1 H), 4.49-4.59 (m, 1 H), 1.72 (d, J = 6.7 Hz, 3 H), 1.36 (dd, J =23.5, 6.3 Hz, 3 H). 457: (R)-3-(2-(((S)-1-(1-(3-chloro-4- (CDCl₃) 10.97(d, J = 7.4 Hz, 1 H), LCMS m/z fluorophenyl)-1H-imidazol-4- 8.33 (s, 1H), 7.99 (d, J = 6.7 Hz, 1 449.1 (M + H)⁺,yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- H), 7.90 (d, J = 7.0 Hz, 1 H),7.50-7.65 Rt 0.63 min; fluoroethyl)oxazolidin-2-one (m, 2 H), 7.37 (d, J= 5.9 Hz, 2 HPLC 2.193 min. H), 5.53 (t, J = 6.7 Hz, 1 H), 4.87-5.19 (m,2 H), 4.60-4.70 (m, 1 H), 4.44-4.59 (m, 1 H), 1.71 (d, J = 6.7 Hz, 3 H),1.36 (dd, J = 23.5, 5.9 Hz, 3 H). 458: (R)-3-(2-(((S)-1-(1-(4-chloro-3-(CDCl₃) 10.94 (d, J = 7.0 Hz, 1 H), LCMS m/zfluorophenyl)-1H-imidazol-4- 8.27 (s, 1 H), 7.98 (d, J = 7.0 Hz, 1 449.2(M + H)⁺, yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- H), 7.88 (d, J = 6.7Hz, 1 H), 7.62 (t, Rt 0.64 min; fluoroethyl)oxazolidin-2-one J = 8.0 Hz,1 H), 7.55 (s, 1 H), 7.31 HPLC 2.279 min. (dd, J = 9.0, 2.3 Hz, 1 H),7.23 (br. s., 1 H), 5.48 (t, J = 6.8 Hz, 1 H), 4.83-5.19 (m, 2 H),4.60-4.69 (m, 1 H), 4.46-4.58 (m, 1 H), 1.70 (d, J = 6.7 Hz, 3 H), 1.35(dd, J = 23.5, 6.3 Hz, 3 H). 459: (R)-3-(2-(((S)-1-(1-(3,4- (CDCl₃)10.96 (d, J = 7.0 Hz, 1 H), LCMS m/z difluorophenyl)-1H-imidazol-4- 8.27(s, 1 H), 7.98 (d, J = 7.0 Hz, 1 433.2 (M + H)⁺,yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- H), 7.89 (d, J = 7.0 Hz, 1 H),7.53 Rt 0.59 min; fluoroethyl)oxazolidin-2-one (s, 1 H), 7.31-7.45 (m, 2H), 5.51 HPLC 1.870 min. (t, J = 6.7 Hz, 1 H), 4.84-5.19 (m, 2 H),4.60-4.72 (m, 1 H), 4.43-4.58 (m, 1 H), 1.70 (d, J = 6.7 Hz, 3 H), 1.36(dd, J = 23.5, 6.3 Hz, 3 H). 460: (R)-3-(2-(((S)-1-(2,5-difluoro-4-(1-(CDCl₃) 10.96 (d, J = 6.7 Hz, 1 H), LCMS m/z methyl-1H-pyrazol-4- 7.99(d, J = 7.0 Hz, 1 H), 7.71-7.89 447.3 (M + H)⁺,yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4- (m, 3 H), 7.20 (ddd, J = 14.6,10.7, Rt 0.68 min; ((S)-1-fluoroethyl)oxazolidin-2-one 6.1 Hz, 2 H),5.33 (quin, J = 6.7 Hz, HPLC 2.612 min. 1 H), 4.64-4.77 (m, 2 H),4.52-4.64 (m, 2 H), 4.45-4.51 (m, 1 H), 3.99 (s, 3 H), 1.64 (d, J = 7.0Hz, 3 H), 1.23 (dd, J = 23.5, 6.7 Hz, 3 H). 461:(R)-3-(5-fluoro-2-(((S)-1-(1-(4- (CD3OD) 9.32 (s, 1 H), 8.33 (d, LCMS(B) fluorophenyl)-1H-imidazol-4- J = 2.7 Hz, 1 H), 7.94 (s, 1 H), 7.72m/z 433.1; yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- (dd, J = 9.0, 4.3Hz, 2 H), 7.37 (t, Rt = 0.60 min. fluoroethyl)oxazolidin-2-one J = 8.4Hz, 2 H), 5.21 (q, J = 6.4 Hz, 1 H), 4.78-4.95 (m, 2 H), 4.63 (t, J =9.2 Hz, 1 H), 4.41 (dd, J = 9.2, 4.5 Hz, 1 H), 1.70 (d, J = 7.0 Hz, 3H), 1.12-1.29 (m, 3H) 462: (R)-3-(5-fluoro-2-(((S)-1-(5-fluoro-2′-(CD3OD) 8.74-8.84 (m, 2 H), LCMS (B)(trifluoromethyl)-[3,4′-bipyridin]-6- 8.24 (br. s., 1 H), 8.14 (s, 1 H),m/z 513.2; yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- 8.09 (dd, J = 10.8,1.4 Hz, 1 H), Rt = 0.87 min fluoroethyl)oxazolidin-2-one 7.97 (d, J =4.7 Hz, 1 H), 5.41 (d, J = 6.3 Hz, 1 H), 4.75-4.94 (m, 2 H), 4.60 (t, J= 9.2 Hz, 1 H), 4.41 (dd, J = 9.2, 4.9 Hz, 1 H), 1.59 (d, J = 7.0 Hz,3H), 1.04 (br. s., 3 H) 463: (R)-3-(2-(((S)-1-(5-fluoro-2′- (CD3OD) 8.87(s, 1 H), 8.82 (d, LCMS (B) (trifluoromethyl)-[3,4′-bipyridin]-6- J =5.1 Hz, 1 H), 8.15-8.27 (m, 3 m/z 495.2;yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- H), 8.00 (d, J = 4.7 Hz, 1 H),7.81 Rt = 0.75 min fluoroethyl)oxazolidin-2-one (d, J = 6.7 Hz, 1 H),5.63 (d, J = 5.5 Hz, 1 H), 4.75-5.02 (m, 2 H), 4.64 (dd, J = 9.0, 2.7Hz, 1 H), 4.48-4.58 (m, 1 H), 1.68 (d, J = 7.0 Hz, 3 H), 1.21-1.46 (m, 3H) 464: (R)-3-(2-(((S)-1-(5-fluoro-2′- (CD3OD) 8.76-8.88 (m, 2 H), LCMS(B) (trifluoromethyl)-[3,4′-bipyridin]-6- 8.11-8.25 (m, 3 H), 7.99 (d, J= 5.1 m/z 495.2; yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1- Hz, 1 H), 7.67(d, J = 4.7 Hz, 1 H), Rt = 0.75 min fluoroethyl)oxazolidin-2-one 5.57(d, J = 6.7 Hz, 1 H), 5.10 (br. s., 1 H), 4.76-4.96 (m, 2 H), 4.47-4.62(m, 2 H), 1.67 (d, J = 6.7 Hz, 3 H), 0.92-1.21 (m, 3 H) 465:(R)-3-(5-fluoro-2-(((S)-1-(5-fluoro-2′- (CD3OD) 8.73-8.86 (m, 2 H), LCMS(B) (trifluoromethyl)-[3,4′-bipyridin]-6- 8.24 (br. s., 1 H), 8.16 (s, 1H), m/z 513.2; yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1- 8.11 (d, J =11.0 Hz, 1 H), 7.98 (d, Rt = 0.95 min fluoroethyl)oxazolidin-2-one J =5.1 Hz, 1 H), 5.43 (d, J = 6.7 Hz, 1 H), 4.85 (s, 2 H), 4.61 (t, J = 9.0Hz, 1 H), 4.42-4.52 (m, 1 H), 1.58 (d, J = 7.0 Hz, 3 H), 1.17 (d, J =19.2 Hz, 3 H)

Example 466(R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

Example 466 was prepared by a convergent route. Steps 1a-1c give(S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine.Steps 2a-2f give(R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one.These intermediates were combined in Step 3 to give(R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one.

Step 1a: To a solution of (S)-1-(5-bromo-4-methylpyridin-2-yl)ethanaminehydrochloride (750 mg, 2.98 mmol) in DCM (30 mL) was added di-tert-butyldicarbonate (0.761 mL, 3.28 mmol) and triethylamine (1.25 mL, 8.94mmol). The resulting solution was stirred at r.t. overnight. Mixture wasconcentrated under reduced pressure and diluted with 40 mL EtOAc, washedwith water, brine, dried over Na₂SO₄ and concentrated to give 940 mg of(S)-tert-butyl (1-(5-bromo-4-methylpyridin-2-yl)ethyl)carbamate as alight brown oil. MS m/z 317.2 (M+H). ¹H NMR (400 MHz, CDCl₃) δ 8.57 (s,1H), 7.14 (s, 1H), 5.57-5.50 (m, 1H), 4.79 (p, J=7.0 Hz, 1H), 2.40 (s,3H), 1.47-1.43 (m, 12H).

Step 1b: N₂ was bubbled through a solution of (S)-tert-butyl(1-(5-bromo-4-methylpyridin-2-yl)ethyl)carbamate (200 mg, 0.635 mmol),(2-(trifluoromethyl)pyridin-4-yl)boronic acid (145 mg, 0.761 mmol) andNa₂CO₃ (2.0 M, 635 μl, 1.269 mmol) in dioxane for 5 min. Cl₂Pd(dppf)(CH₂Cl₂ adduct) (51.8 mg, 0.063 mmol) was added. The reaction mixturewas stirred at 90° C. for 16 hr. The mixture was diluted with EtOAc,washed with water, brine, dried over Na₂SO₄, filtered, concentrated andpurified through flash column chromatography (0-100% EtOAc/Heptane) togive 200 mg (S)-tert-butyl(1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)carbamateas a white solid. 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J=4.9 Hz, 1H), 8.36(s, 1H), 7.66 (s, 1H), 7.51-7.42 (m, 1H), 7.21 (s, 1H), 5.60 (d, J=7.7Hz, 1H), 4.87 (p, J=6.9 Hz, 1H), 2.30 (s, 3H), 1.48 (d, J=6.9 Hz, 3H),1.45 (s, 9H). MS m/z 382.3 (M+H).

Step 1c: To a solution of (S)-tert-butyl(1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)carbamate(200 mg, 0.524 mmol) in DCM (2 ml) at −78° C. was added trifluoroaceticacid (2 mL, 12.98 mmol). The solution was stirred at r.t. for 1 hr. Themixture was concentrated, diluted with 10 mL DCM and stirred with solidMP-carbonate to remove TFA. Filtered and concentrated to give 147 mg(S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine asa light brown sticky oil. MS m/z 282.1 (M+H). Rt=0.85 min. (Column:XBridge C18 3.5 um 2.1×50 mm. Solvent A: 2% Acetonitrile, 3.75 mMAmmonium Acetate, Water. Solvent B: Acetonitrile. Gradient: 5-95% B over1.70 min. Flow rate: 2 mL/min.) The crude product was used to next stepwithout further purification.

Step 2a: A solution of(2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)butanoic aciddicyclohexylammonium salt (500 mg, 1.0 mmol) in 10 ml of THF andisobutyl chloroformate (167 mg, 1.2 mmol, 1.2 equiv) at −25° C. wasadded N-methylmorpholine (124 mg, 1.2 mmol, 1.2 equiv), the mixture wasstirred at same temperature for 10 min and filtered. The filtrate wascooled to −20° C. and to it was added NaBH₄, followed by 2 ml of waterimmediately afterwards. The reaction mixture was stirred at sametemperature for 5 min. then gradually warmed to room temperature for 25min, poured into water (10 ml) and extracted with ethyl acetate (2×20ml). The combined organic phases were washed with water, brine and driedover Na₂SO₄. The solvent was removed to yield benzyl((2R)-(3R)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate as a clear oil.No further purification was required for next step. ¹H NMR (400 MHz,CDCl₃) δ 7.37-7.16 (m, 5H), 5.25 (d, J=8.0 Hz, 1H), 5.02 (s, 1H), 4.04(ddd, J=12.0, 8.9, 2.8 Hz, 1H), 3.92-3.75 (m, 1H), 3.59 (dddd, J=32.3,14.6, 8.2, 4.3 Hz, 2H), 1.10 (s, 9H), 1.09-1.06 (m, 3H).

Step 2b: To a solution of benzyl((2R,3R)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (5.88 g, 19.9mmol) in 100 mL DMF was added NaH (60% in mineral oil, 1.62 g, 40.6mmol) at 0° C. The reaction mixture was stirred for 30 min at 0° C. Tothe reaction mixture were added 4-methoxybenzyl chloride (4.07 mL, 29.9mmol) and tetrabutylammonium iodide (0.74 g, 1.99 mmol) and theresulting mixture was warmed to room temperature and stirred for 15.5 h.The reaction mixture was poured into ice water (200 mL) forming a whitesuspension. EtOAc (100 mL) was added and the resulting mixture wasstirred for 5 min to form a clear two layer solution. After separation,the aqueous phase was extracted with EtOAc (100 mL×3). The combinedorganic solution was washed with brine (80 mL), dried over Na₂SO₄,filtered and concentrated. Flash column chromatography (EtOAc/Heptane 0to 70%) gave 5.90 g of(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(4-methoxybenzyl)oxazolidin-2-onewith minor impurities. Major product 1H NMR (400 MHz, MeOD) δ 7.38-7.29(m, 2H), 6.99-6.93 (m, 2H), 4.68-4.58 (m, 1H), 4.33 (dd, J=9.3, 4.5 Hz,1H), 4.27-4.17 (m, 2H), 3.89 (dd, J=6.4, 4.8 Hz, 1H), 3.81 (s, 3H), 3.65(dd, J=9.0, 4.6 Hz, 1H), 1.09 (s, 9H), 1.02 (d, J=6.3 Hz, 3H). MS m/z308.2 (M+H).

Step 2c: A solution of(R)-4-((R)-1-(tert-butoxy)ethyl)-3-(4-methoxybenzyl)oxazolidin-2-one(5.90 g, 19.2 mmol) in CH₂Cl₂ (40 mL) was treated with TFA (40 mL) atroom temperature for 20 min. The reaction mixture was concentrated invacuo, then diluted with CH₂Cl₂ (˜50 mL), and again concentrated. Thisprocedure was repeated three times to remove TFA. Flash columnchromatography (EtOAc/Heptane 30 100%) gave 3.81 g(R)-4-((R)-1-hydroxyethyl)-3-(4-methoxybenzyl)oxazolidin-2-one. 1H NMR(400 MHz, MeOD) δ 7.31-7.21 (m, 2H), 7.00-6.87 (m, 2H), 4.67 (d, J=15.0Hz, 1H), 4.34-4.18 (m, 3H), 3.95 (q, J=6.2 Hz, 1H), 3.80 (s, 3H), 3.68(dt, J=8.7, 5.5 Hz, 1H), 1.09 (d, J=6.4 Hz, 3H). MS m/z 252.2 (M+H).

Step 2d: To a cooled (0° C.) solution of(R)-4-((R)-1-hydroxyethyl)-3-(4-methoxybenzyl)oxazolidin-2-one (2.27 g,9.04 mmol) in 30 mL MeCN were added triethylamine (11.4 mL, 82 mmol)followed by perfluoro-1-butanesulfonyl fluoride (4.9 mL, 27.3 mmol) andNEt₃(HF)₃ (4.5 mL, 27.6 mmol) and the resulting mixture was stirred at0° C. for 70 min. The reaction mixture was diluted with water (60 mL)and extracted with EtOAc (3×60 mL). Combined organics were washed withwater (70 mL), brine (70 mL), dried over Na₂SO₄, filtered andconcentrated. Flash column chromatography (EtOAc/heptane 5 to 70%) gave2.19 g (R)-4-((S)-1-fluoroethyl)-3-(4-methoxybenzyl)oxazolidin-2-one. 1HNMR (400 MHz, CDCl3) δ 7.25-7.20 (m, 2H), 6.92-6.83 (m, 2H), 4.87 (d,J=15.1 Hz, 1H), 4.75 (dqd, J=47.6, 6.6, 2.1 Hz, 1H), 4.26 (td, J=9.2,1.4 Hz, 1H), 4.17-4.05 (m, 2H), 3.81 (s, 3H), 3.71 (dddd, J=19.8, 9.5,5.8, 2.1 Hz, 1H), 1.29 (dd, J=23.1, 6.2 Hz, 3H). MS m/z 254.5 (M+H).

Step 2e: A solution of(R)-4-((S)-1-fluoroethyl)-3-(4-methoxybenzyl)oxazolidin-2-one (1.98 g7.8 mmol) in 40 mL TFA was heated at 65° C. for 16 h. The reactionmixture was concentrated to remove TFA. Flash column chromatography(EtOAc/CH₂Cl₂, 0 to 100%) gave 0.91 g(R)-4-((S)-1-fluoroethyl)-oxazolidin-2-one as a pale brown solid. TLC(1:2 heptane:EtOAc) Rf=0.25. 1H NMR (400 MHz, CDCl3) δ 5.60 (br s, 1H),4.72-4.54 (m, 1H), 4.51 (td, J=8.9, 0.9 Hz, 1H), 4.32 (dd, J=9.2, 4.8Hz, 1H), 4.02-3.88 (m, 1H), 1.38 (dd, J=24.0, 6.3 Hz, 3H).

Step 2f: To a cooled (0° C.) solution of 2,4-difluoropyrimidine (160 mg,1.375 mmol) and (R)-4-((S)-1-fluoroethyl)oxazolidin-2-one (183 mg, 1.375mmol) in DMF (Volume: 4.6 mL) was added NaH (60% in mineral oil, 66.0mg, 1.650 mmol). The resulting mixture was stirred at 0° C. for 30 minand at room temperature for 2 hr. Desired product was observed fromLC-MS. The mixture was quenched with brine (1 ml). Diluted w/ EtOAc (20ml) and water (10 ml), and separated layers. The organic was extractedwith an additional 20 mL EtOAc. The combined organics were washed withbrine, dried, and concentrated. Crude was purified through flash columnchromatography (10-100% EtOAc/Heptane) to give 210 mg(R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one asa white solid. 1H NMR (400 MHz, CDCl3) δ 8.51 (dd, J=5.8, 2.1 Hz, 1H),8.20 (dd, J=5.7, 3.7 Hz, 1H), 5.33 (dqd, J=49.5, 6.6, 1.3 Hz, 1H), 4.77(dddd, J=26.5, 9.1, 3.4, 1.4 Hz, 1H), 4.65 (dd, J=9.0, 3.4 Hz, 1H), 4.50(td, J=9.0, 1.3 Hz, 1H), 1.43 (dd, J=23.1, 6.6 Hz, 3H). MS m/z 230.1(M+H).

Step 3: A solution of(S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine(28.1 mg, 0.1 mmol),(R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one(22.9 mg, 0.100 mmol) and DIPEA (52.4 μl, 0.300 mmol) in DMSO (Volume:500 μl) was heated at 110° C. for 1 hr. The solution was then cooled tort, and RP-HPLC (acetonitrile:water) purification provided a whitesolid. This material was purified again with flash column chromatography(0-10% MeOH/EtOAc) to give 14 mg(R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-oneas a white solid. 1H NMR (400 MHz, MeOD) δ 8.81 (d, J=5.0 Hz, 1H), 8.41(s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 7.69 (dd, J=5.0, 1.6 Hz, 1H), 7.44(s, 1H), 7.41 (d, J=5.8 Hz, 1H), 5.08 (br s, 1H), 4.73 (br d, J=26.0 Hz,1H), 4.56-4.27 (m, 3H), 2.32 (s, 3H), 1.58 (d, J=7.1 Hz, 3H), 1.12 (brs, 3H); HRMS (B) m/z 491.1782 (M+H)⁺. Anal. RP-HPLC t_(R)=3.42 min.Purity 100%/100%.

Example 467(R)-3-(2-(((S)-1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

(R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (50mg, 0.218 mmol) and(S)-1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanamine(75 mg, 0.262 mmol) were taken up in 3 mL DMSO. Hunig's base (57 uL,0.327 mmol) was added. The mixture was heated to 110 C for 1.5 h. Thereaction mixture was poured into 30 mL water, and extracted with EtOAc(2×30 mL). Organics were washed with 20 mL each water, and brine.Combined organics were dried over Na₂SO₄, filtered and concentrated onsilica gel. Column chromatography (25-100% EtOAc/heptane) gave 82 mgwhite solid. ¹H NMR (400 MHz, CDCl₃) δ 8.91 (d, J=1.4 Hz, 2H), 8.25 (d,J=5.7 Hz, 1H), 7.79-7.61 (m, 2H), 7.52 (d, J=5.7 Hz, 1H), 7.44 (tt,J=7.7, 0.8 Hz, 1H), 6.12 (s, 1H), 5.32 (s, 1H), 5.08 (br s, 1H), 4.80(dddd, J=26.5, 9.1, 3.4, 1.5 Hz, 1H), 4.58 (dd, J=8.8, 3.4 Hz, 1H), 4.44(td, J=9.0, 1.3 Hz, 1H), 1.68 (d, J=8.8 Hz, 3H), 1.43-1.24 (m, 3H). HRMS(A) m/z 495.1611 (M+H)⁺. Anal. RP-HPLC t_(R)=3.68 min. Purity 96%/100%.

Example 468(R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

A solution of(S)-1-(2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine (27 mg,0.10 mmol),(R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (23mg, 0.10 mmol) and DIPEA (52.4 μl, 0.30 mmol) in DMSO (500 μl) washeated at 110° C. for 1 hr. The solution was then cooled to rt andRP-HPLC purification (acetonitrile:water) provided the 32 mg of themajor product as a white solid. 1H NMR (400 MHz, MeOD) δ 8.98 (s, 1H),8.79 (d, J=5.1 Hz, 1H), 8.23 (dd, J=8.2, 2.4 Hz, 1H), 8.17 (br s, 1H),8.17-8.12 (m, 1H), 7.98 (dd, J=5.1, 1.7 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H),7.40 (d, J=5.8 Hz, 1H), 5.11 (br s, 1H), 4.69 (br d, J=27.2 Hz, 1H),4.55-4.12 (m, 3H), 1.60 (d, J=7.1 Hz, 3H), 1.03 (br s, 3H); HRMS (B) m/z477.1699 (M+H)⁺.

Example 469(R)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

(R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (50mg, 0.218 mmol),(S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethanamine (60.5 mg,0.262 mmol), and DIPEA (57 ul, 0.327 mmol) were taken up in 3 mL DMSO.Heated to 110 C for 1 h. The reaction mixture was poured into 30 mLwater and extracted with EtOAc (2×30 mL). Organics were washed with 20mL each water, brine, and dried over Na₂SO₄, and filtered andconcentrated on silica gel. Column chromatography (25-100% EtOAc/hept)gave the desired product (92 mg) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.87 (s, 2H), 8.25 (d, J=5.7 Hz, 1H), 7.51 (d, J=5.7 Hz, 1H),7.42-7.31 (m, 2H), 7.21-7.12 (m, 1H), 6.15 (s, 1H), 5.28 (s, 2H), 4.80(dddd, J=26.6, 9.0, 3.5, 1.6 Hz, 1H), 4.57 (dd, J=8.8, 3.4 Hz, 1H), 4.44(td, J=9.0, 1.3 Hz, 1H), 2.39 (d, J=1.9 Hz, 3H), 1.66 (d, J=6.9 Hz, 3H),1.35-1.24 (m, 3H). HRMS (A) m/z 441.1849 (M+H)⁺. Anal. RP-HPLCt_(R)=3.10 min. Purity 100%/100%.

Example 470(R)-3-(5-fluoro-2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

A solution of(S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine(50 mg, 0.178 mmol),(R)-3-(2,5-difluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one,(46.1 mg, 0.187 mmol) and DIPEA (93 μl, 0.533 mmol) in DMSO (889 μl) washeated at 110° C. for 1 hr. The the solution was then cooled to rtdiluted with 10 mL EtOAc, washed with water, brine, dried over Na₂SO₄,concentrated and purified through RP-HPLC (acetonitrile:water) toprovide 37 mg white solid. 1H NMR (400 MHz, MeOD) δ 8.81 (d, J=5.0 Hz,1H), 8.39 (s, 1H), 8.26 (s, 1H), 7.85 (s, 1H), 7.69 (dd, J=5.1, 1.6 Hz,1H), 7.46 (s, 1H), 5.00 br (s, 1H), 4.66-4.37 (m, 4H), 2.32 (s, 3H),1.57 (d, J=7.1 Hz, 3H), 1.04 (br s, 3H); HRMS (B) m/z 509.1701 (M+H)⁺.

Example 471(R)-4-(fluoromethyl)-3-(2-(((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

A solution of(R)-4-(fluoromethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (15 mg,0.070 mmol), (S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethanaminehydrochloride (20 mg, 0.084 mmol, 1.2 equiv), andN-ethyl-N-isopropylpropan-2-amine (0.043 mL, 0.24 mmol, 3.5 equiv) inDMSO (1.0 mL) was heated at 85° C. for 14 hours. The reaction was thencooled to room temperature. Purification by reverse phase HPLC providedthe trifluoroacetate salt of(R)-4-(fluoromethyl)-3-(2-(((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one(6 mg, white solid) in 17% yield. ¹H NMR (400 MHz, CDCl₃) δ 11.11 (d,J=6.9 Hz, 1H), 8.40 (s, 1H), 7.97 (d, J=7.0 Hz, 1H), 7.88 (d, J=6.9 Hz,1H), 7.62 (s, 1H), 7.47 (dd, J=8.7, 4.3 Hz, 2H), 7.28-7.34 (m, 2H), 5.75(t, J=7.1 Hz, 1H), 5.20-5.33 (m, 1H), 4.45-4.75 (m, 4H), 1.71 (d, J=6.8Hz, 3H); HRMS (A) m/z 401.1537 (M+H)⁺; Rt-1.22 min.

Example 472(R)-3-(2-(((S)-1-(1-(3-chloro-4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one

A solution of(R)-3-(2,5-difluoropyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one (15mg, 0.064 mmol),(S)-1-(1-(3-chloro-4-fluorophenyl)-1H-imidazol-4-yl)ethanaminehydrochloride (21 mg, 0.077 mmol, 1.2 equiv), andN-ethyl-N-isopropylpropan-2-amine (0.039 mL, 0.23 mmol, 3.5 equiv) inDMSO (1.0 mL) was heated at 85° C. for 14 hours. The reaction was thencooled to room temperature. Purification by reverse phase HPLC providedthe trifluoroacetate salt of(R)-3-(2-(((S)-1-(1-(3-chloro-4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one(11 mg, white solid) in 30% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s,1H), 8.18 (d, J=1.9 Hz, 1H), 7.57-7.63 (m, 1H), 7.33-7.48 (m, 3H), 5.34(br. s., 1H), 4.85-5.00 (m, 1H), 4.41-4.75 (m, 4H), 1.73 (d, J=7.0 Hz,3H); HRMS (A) m/z 453.1058 (M+H)⁺; Rt-1.51 min.

Example 473(R)-3-(2-(((S)-1-(1-(4-chloro-3-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one

A solution of(R)-4-(fluoromethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (15 mg,0.070 mmol),(S)-1-(1-(4-chloro-3-fluorophenyl)-1H-imidazol-4-yl)ethanaminehydrochloride (22 mg, 0.084 mmol, 1.2 equiv), andN-ethyl-N-isopropylpropan-2-amine (0.043 mL, 0.24 mmol, 3.5 equiv) inDMSO (1.0 mL) was heated at 85° C. for 14 hours. The reaction was thencooled to room temperature. Purification by reverse phase HPLC providedthe trifluoroacetate salt of(R)-3-(2-(((S)-1-(1-(4-chloro-3-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one(14 mg, white solid) in 35% yield. ¹H NMR (400 MHz, CDCl₃) δ 11.04 (d,J=7.0 Hz, 1H), 8.29 (s, 1H), 7.97 (d, J=7.1 Hz, 1H), 7.86 (d, J=6.9 Hz,1H), 7.57-7.67 (m, 2H), 7.32 (dd, J=8.7, 2.5 Hz, 1H), 7.24 (d, J=1.0 Hz,1H), 5.64 (t, J=7.1 Hz, 1H), 5.12-5.27 (m, 1H), 4.43-4.75 (m, 4H), 1.70(d, J=6.8 Hz, 3H); HRMS (A) m/z 435.1151 (M+H)⁺; Rt-1.51 min.

Example 474(R)-3-(2-(((S)-1-(1-(3,4-difluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one

A solution of(R)-4-(fluoromethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (15 mg,0.070 mmol), (S)-1-(1-(3,4-difluorophenyl)-1H-imidazol-4-yl)ethanaminehydrochloride (22 mg, 0.084 mmol, 1.2 equiv), andN-ethyl-N-isopropylpropan-2-amine (0.043 mL, 0.24 mmol, 3.5 equiv) inDMSO (1.0 mL) was heated at 85° C. for 14 hours. The reaction was thencooled to room temperature. Purification by reverse phase HPLC providedthe trifluoroacetate salt of(R)-3-(2-(((S)-1-(1-(3,4-difluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one(10 mg, white solid) in 26% yield. ¹H NMR (400 MHz, CDCl₃) δ 11.05 (d,J=8.2 Hz, 1H), 8.30 (s, 1H), 7.98 (d, J=7.2 Hz, 1H), 7.87 (d, J=7.0 Hz,1H), 7.59 (s, 1H), 7.31-7.46 (m, 2H), 7.24 (br. s., 1H), 5.61-5.71 (m,1H), 5.14-5.28 (m, 1H), 4.44-4.76 (m, 4H), 1.70 (d, J=6.8 Hz, 3H);HRMS(A) m/z 419.1444 (M+H)⁺; Rt-1.35 min.

Example 475(R)-3-(2-(((S)-1-(1-(4-(difluoromethyl)-3-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one

A solution of(R)-4-(fluoromethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (15 mg,0.070 mmol),(S)-1-(1-(4-(difluoromethyl)-3-fluorophenyl)-1H-imidazol-4-yl)ethanaminehydrochloride (24 mg, 0.084 mmol, 1.2 equiv), andN-ethyl-N-isopropylpropan-2-amine (0.043 mL, 0.24 mmol, 3.5 equiv) inDMSO (1.0 mL) was heated at 85° C. for 14 hours. The reaction was thencooled to room temperature. Purification by reverse phase HPLC providedthe trifluoroacetate salt of(R)-3-(2-(((S)-1-(1-(4-(difluoromethyl)-3-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one(15 mg, white solid) in 37% yield. ¹H NMR (400 MHz, CDCl₃) δ 10.99 (d,J=7.2 Hz, 1H), 8.24 (s, 1H), 7.97 (d, J=6.8 Hz, 1H), 7.78-7.87 (m, 2H),7.61 (s, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.31 (d, J=1.0 Hz, 1H), 6.79-7.09(m, 1H), 5.57 (t, J=7.0 Hz, 1H), 5.09-5.23 (m, 1H), 4.44-4.77 (m, 4H),1.70 (d, J=6.9 Hz, 3H); HRMS(A) m/z 451.1512 (M+H)⁺; Rt-1.48 min.

Example 476(R)-3-(2-(((S)-1-(1-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

Step 1: Preparation of(S)-1-(1-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)ethanamineHydrochloride

To 1H-imidazole-4-carbaldehyde (2.56 g, 26.6 mmol),4-chloro-2-fluoro-1-iodobenzene (0.739 g, 2.88 mmol) and Cs₂CO₃ (1.564g, 4.80 mmol) in DMF (50 mL) was added copper(I) iodide (0.023 g, 0.120mmol) and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.068 g, 0.480mmol). The reaction was heated to 110° C. for 18 hours. The reactionmixture was then cooled to room temperature and filtered, and washedwith EtOAc (100 mL). The organic was washed with water (2×30 mL) andbrine (30 mL), dried (Na₂SO₄) and concentrated. The residue was purifiedby silica gel chromotography to give1-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carbaldehyde (451 mg), towhich was added (S)-2-methylpropane-2-sulfinamide (0.29 g, 2.4 mmol),CuSO₄ (0.638 g, 4 mmol) and DCE (10 mL). The reaction was heated to 65°C. for 18 hours. The reaction was cooled to rt, filtered andconcentrated to give(S,E)-N-((1-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide,to which was added DCM (20 mL). The reaction mixture was cooled to −70°C. and methylmagnesium bromide (1.33 ml, 4 mmol) was added dropwise tothe solution. The reaction was stirred for two hours and the cold bathwas then removed, and the reaction was allowed to warm to rt and stirfor 30 minutes. The reaction was cooled to 0° C. and HCl (1M) was addedcautiously to quench until aqueous pH=8. The phases were separated andthe aqueous layer was extracted with DCM (2×30 mL). Combined organic wasdried (Na2SO4) and concentrated to give(S)—N—((S)-1-(1-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide(130 mg), which was then dissolved in MeOH (5 mL) and HCl (0.5 mL, 4M)was added. The reaction was stirred for one hour and concentrated togive product (100 mg). LCMS m/z 240.1 (M+H)⁺; Rt-0.50 min.

Step 2: Preparation of(R)-3-(2-(((S)-1-(1-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

A solution of(S)-1-(1-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)ethanaminehydrochloride (20 mg, 0.072 mmol),(S)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (15mg, 0.065 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.040 mL, 0.23mmol) in DMSO (0.5 mL) was heated at 90° C. for 8 hours. The reactionwas then cooled to room temperature. Purification by reverse phase HPLCprovided the trifluoroacetate salt of(R)-3-(2-(((S)-1-(1-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one(12 mg). ¹H NMR (400 MHz, CD₃OD) δ 8.68 (br. s., 1H), 8.22 (d, J=6.7 Hz,1H), 7.76 (d, J=4.7 Hz, 1H), 7.70-7.55 (m, 3H), 7.45 (d, J=8.6 Hz, 1H),5.36-5.24 (m, 1H), 4.9-4.75 (m, 2H), 4.62 (dd, J=2.7, 9.4 Hz, 1H),4.56-4.47 (m, 1H), 1.71 (d, J=6.7 Hz, 3H), 1.35-1.17 (m, 3H); HRMS(A)m/z 449.1306 (M+H)⁺; Rt-1.57 min.

Example 477(R)-3-(2-(((S)-1-(1-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

A solution of(S)-1-(1-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)ethanaminehydrochloride (20 mg, 0.072 mmol),(R)-3-(2,5-difluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one(15 mg, 0.061 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.040 mL,0.23 mmol) in DMSO (0.5 mL) was heated at 90° C. for 8 hours. Thereaction was then cooled to room temperature. Purification by reversephase HPLC provided the trifluoroacetate salt of(R)-3-(2-(((S)-1-(1-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one(10 mg). ¹H NMR (400 MHz, CD₃OD) δ 8.25 (d, J=3.1 Hz, 1H), 7.96 (s, 1H),7.58-7.45 (m, 2H), 7.36 (d, J=8.6 Hz, 1H), 7.26 (s, 1H), 5.06 (d, J=6.7Hz, 1H), 4.9-4.75 (m, 2H), 4.67-4.55 (m, 2H), 4.53-4.43 (m, 1H), 1.57(d, J=7.0 Hz, 3H), 1.26-1.06 (m, 3H); HRMS(A) m/z 467.1217 (M+H)⁺;Rt-1.66 min.

Example 478(R)-3-(2-(((S)-1-(1-(2,4-difluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

Step 1: Preparation of(S)-1-(1-(2,4-difluorophenyl)-1H-imidazol-4-yl)ethanamine Hydrochloride

To 1H-imidazole-4-carbaldehyde (3.01 g, 31.3 mmol),2,4-difluoro-1-iodobenzene (1.008 g, 4.20 mmol), Cs₂CO₃ (2.281 g, 7.00mmol) in DMF (50 mL) was added copper(I) iodide (0.033 g, 0.175 mmol)and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.100 g, 0.700 mmol).The reaction was heated to 110° C. for 18 hours. The reaction mixturewas then cooled to room temperature and filtered, and washed with EtOAc(100 mL). The organic was washed with water (2×30 mL) and brine (30 mL),dried (Na₂SO₄) and concentrated. The residue was purified by silica gelchromotography to give1-(2,4-difluorophenyl)-1H-imidazole-4-carbaldehyde (651 mg), to whichwas added (S)-2-methylpropane-2-sulfinamide (0.424 g, 3.5 mmol), CuSO₄(0.798 g, 5 mmol) and DCE (10 mL). The reaction was heated to 65° C. for18 hours. The reaction was cooled to rt, filtered and concentrated togive(S,E)-N-((1-(2,4-difluorophenyl)-1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide,to which was added DCM (20 mL). The reaction mixture was cooled to −70°C. and methylmagnesium bromide (1.667 ml, 5 mmol) was added dropwise tothe solution. The reaction was stirred for two hours and the cold bathwas then removed, and the reaction was allowed to warm to rt and stirfor 30 minutes. The reaction was cooled to 0° C. and HCl (1M) was addedcautiously to quench until aqueous pH=8. The phases were separated andthe aqueous layer was extracted with DCM (2×30 mL). Combined organic wasdried (Na₂SO₄) and concentrated to give(S)—N—((S)-1-(1-(2,4-difluorophenyl)-1H-imidazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide(230 mg), which was then dissolved in MeOH (5 mL) and HCl (0.5 mL, 4M)was added. The reaction was stirred for one hour and concentrated togive product (212 mg). LCMS m/z 224.1 (M+H)⁺; Rt-0.39 min.

Step 2: Preparation of(R)-3-(2-(((S)-1-(1-(2,4-difluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

A solution of (S)-1-(1-(2,4-difluorophenyl)-1H-imidazol-4-yl)ethanaminehydrochloride (18 mg, 0.069 mmol),(S)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (13mg, 0.057 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.040 mL, 0.23mmol) in DMSO (0.5 mL) was heated at 90° C. for 8 hours. The reactionwas then cooled to room temperature. Purification by reverse phase HPLCprovided the trifluoroacetate salt of(R)-3-(2-(((S)-1-(1-(2,4-difluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one(10 mg). ¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J=6.7 Hz, 1H), 7.88 (q,J=8.7 Hz, 6H), 7.71 (d, J=5.5 Hz, 1H), 5.27 (d, J=7.0 Hz, 1H), 4.86 (s,2H), 4.68-4.44 (m, 2H), 1.71 (d, J=7.0 Hz, 3H), 1.34-1.15 (m, 3H);HRMS(A) m/z 433.1603 (M+H)⁺; Rt-1.40 min.

Example 479(R)-3-(2-(((S)-1-(1-(2,4-difluorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one

A solution of (S)-1-(1-(2,4-difluorophenyl)-1H-imidazol-4-yl)ethanaminehydrochloride (18 mg, 0.069 mmol),(R)-3-(2,5-difluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one(15 mg, 0.061 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.040 mL,0.23 mmol) in DMSO (0.5 mL) was heated at 90° C. for 8 hours. Thereaction was then cooled to room temperature. Purification by reversephase HPLC provided the trifluoroacetate salt of(R)-3-(2-(((S)-1-(1-(2,4-difluorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one(18 mg). ¹H NMR (400 MHz, CD₃OD) δ 9.18 (s, 1H), 8.33 (d, J=3.1 Hz, 1H),7.82 (s, 1H), 7.74 (dt, J=5.7, 8.7 Hz, 1H), 7.39 (ddd, J=2.5, 8.5, 10.9Hz, 1H), 7.24 (t, J=8.4 Hz, 1H), 5.21 (d, J=6.7 Hz, 1H), 5.06-4.77 (m,2H), 4.63 (t, J=9.0 Hz, 1H), 4.50 (dd, J=5.9, 8.6 Hz, 1H), 1.69 (d,J=6.7 Hz, 3H), 1.35-1.22 (m, 3H); HRMS (A) m/z 451.1514 (M+H)⁺; Rt-1.47min.

Example 480(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one

(R)-3-(2,5-difluoropyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one (105mg, 0.449 mmol), (S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethanamine (100mg, 0.449 mmol), and DIPEA (157 ul, 0.898 mmol) were dissolved in DMSO(1 mL) and the reaction mixture was heated at 120° C. for 2 h. Thereaction mixture was cooled, diluted with EtOAc, washed with water andbrine, and concentrated in vacuo. Column chromatography (5-50%EtOAc/DCM) gave the desired product (169 mg) as a white foam. ¹H NMR(400 MHz, CDCl₃) δ 8.26 (d, J=2.8 Hz, 1H), 7.59-7.50 (m, 2H), 7.45-7.36(m, 2H), 7.25 (s, 1H), 5.66 (d, J=7.6 Hz, 1H), 5.21 (br s, 1H), 4.86(ddddd, J=20.0, 8.6, 7.0, 4.3, 2.8 Hz, 1H), 4.66-4.44 (m, 3H), 4.41 (brs, 1H), 1.71 (d, J=7.0 Hz, 3H). HRMS-Acidic. LC-UV/ESI-MS data wasrecorded on an Acquity LCTp Tof—Rs(FWHM)>12000 Accuracy<5 ppm. Column:Acquity BEHC18 1.7 μm 2.1×50 mm—50° C. Eluent A: Water+0.1% formic acid.Eluent B: Acetonitrile+0.1% formic acid. Gradient: from 0.2 to 98% B in8.05 min—flow 0.9 mL/min. m/z 436.0996 (M+H)⁺. Anal. RP-HPLC t_(R)=3.46min. Purity 100%/100%.

The compounds listed in Table 39 are made using methods similar to thosedescribed for Examples 1-465 and as outlined in the general syntheticprocedures.

TABLE 39 The compounds in Table 39 are prepared following chemistrysimilar to that described for Examples 1-465 or as outlined in theSchemes given above. Example Name

(R)-4-(fluoromethyl)-3-(2- (((S)-1-(1-(4- fluorophenyl)-1H- imidazol-4-yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one

(R)-3-(2-(((S)-1-(1-(3- chloro-4-fluorophenyl)- 1H-imidazol-4-yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- (fluoromethyl)oxazolidin-2-one

(R)-3-(2-(((S)-1-(1-(4- chloro-3-fluorophenyl)- 1H-imidazol-4-yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one

(R)-3-(2-(((S)-1-(1-(3,4- difluorophenyl)-1H- imidazol-4-yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one

(R)-3-(2-(((S)-1-(1-(4- (difluoromethyl)-3- fluorophenyl)-1H-imidazol-4- yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin-2-one

(R)-3-(2-(((S)-1-(1-(4- chloro-2,5- difluorophenyl)-1H- imidazol-4-yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one

(R)-3-(2-(((S)-1-(1-(4- chloro-2,5- difluorophenyl)-1H- imidazol-4-yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- (fluoromethyl)oxazolidin-2-one

(R)-3-(2-(((S)-1-(1-(4- chloro-2,5- difluorophenyl)-1H- imidazol-4-yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(1-(4- chloro-2,5- difluorophenyl)-1H- imidazol-4-yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1-fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(1-(4- chloro-2-fluorophenyl)- 1H-imidazol-4-yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one

(R)-3-(2-(((S)-1-(1-(4- chloro-2-fluorophenyl)- 1H-imidazol-4-yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- (fluoromethyl)oxazolidin-2-one

(R)-3-(2-(((S)-1-(1-(2,4- difluorophenyl)-1H- imidazol-4-yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one

(R)-3-(2-(((S)-1-(1-(2,4- difluorophenyl)-1H- imidazol-4-yl)ethyl)amino)pyrimidin- 4-yl)-4- (fluoromethyl)oxazolidin- 2-one

(R)-3-(2-(((S)-1-(1-(4- chloro-2-fluorophenyl)- 1H-imidazol-4-yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(1-(4- chloro-2-fluorophenyl)- 1H-imidazol-4-yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1-fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(1-(2,4- difluorophenyl)-1H- imidazol-4-yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(1-(2,4- difluorophenyl)-1H- imidazol-4-yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1-fluoroethyl)oxazolidin-2- one

(R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(2′- (trifluoromethyl)-[3,4′-bipyridin]-6- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one

(R)-3-(5-fluoro-2-(((S)-1- (2′-(trifluoromethyl)-[3,4′- bipyridin]-6-yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one

(R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(5-(2-(trifluoromethyl)pyridin-4- yl)pyrimidin-2- yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

(R)-3-(5-fluoro-2-(((S)-1- (5-(2- (trifluoromethyl)pyridin-4-yl)pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2- one

(R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(5-(3- (trifluoromethyl)phenyl)pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one

(R)-3-(5-fluoro-2-(((S)-1- (5-(3- (trifluoromethyl)phenyl) pyrimidin-2-yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one

(R)-3-(5-fluoro-2-(((S)-1- (5-(2-fluoro-3- (trifluoromethyl)phenyl)pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(5-(2- fluoro-3- (trifluoromethyl)phenyl) pyrimidin-2-yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one

(R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(5-(3- (trifluoromethyl)phenyl)pyridin-2- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one

(R)-3-(5-fluoro-2-(((S)-1- (5-(3- (trifluoromethyl)phenyl) pyridin-2-yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one

(R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(5-(4- (trifluoromethyl)phenyl)pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)oxazolidin-2-one

(R)-3-(5-fluoro-2-(((S)-1- (5-(4- (trifluoromethyl)phenyl) pyrimidin-2-yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(5-(4- chloro-3- (trifluoromethyl)phenyl) pyrimidin-2-yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(5-(4- fluoro-3- methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(5-(4- chloro-3- (trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1-fluoroethyl)oxazolidin-2- one

(R)-3-(5-fluoro-2-(((S)-1- (5-(4-fluoro-3- (trifluoromethyl)phenyl)pyrimidin-2- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(5-(4- fluoro-3- methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one

(R)-3-(5-fluoro-2-(((S)-1- (5-(4-fluoro-3- methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(5-(4- chloro-3-fluorophenyl)-4- methylpyrimidin-2-yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(5-(4- chloro-3-fluorophenyl)-4- methylpyrimidin-2-yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1-fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(5-(3- chlorophenyl)-4- methylpyrimidin-2-yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1- fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(5-(3- chlorophenyl)-4- methylpyrimidin-2-yl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1-fluoroethyl)oxazolidin-2- one

(R)-4-((S)-1-fluoroethyl)- 3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′- bipyridin]-6- yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one

(R)-3-(5-fluoro-2-(((S)-1- (4-methyl-2′- (trifluoromethyl)-[3,4′-bipyridin]-6- yl)ethyl)amino)pyrimidin- 4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(2,5- difluoro-4-(4-methyl-1H- imidazol-1-yl)phenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1-fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(2,5- difluoro-4-(1-methyl-1H- pyrazol-4-yl)phenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1-fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(2,5- difluoro-4-(2- methylpyridin-4-yl)phenyl)ethyl)amino) pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(2,5- difluoro-4-(2- methylpyridin-4-yl)phenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1-fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(2,5- difluoro-4-(2- (trifluoromethyl)pyridin-4-yl)phenyl)ethyl)amino)pyri midin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2- one

(R)-3-(2-(((S)-1-(2,5- difluoro-4-(2- (trifluoromethyl)pyridin-4-yl)phenyl)ethyl)amino)-5- fluoropyrimidin-4-yl)-4- ((S)-1-fluoroethyl)oxazolidin-2- one

Biological Assays and Data Mutant IDH1 Biochemical Assay: LC-MSDetection of 2-HG.

Mutant IDH1 R132H catalytic activity was monitored using thequantitative liquid chromatography/mass spectrometry (LC-MS) detectionof 2-HG, a product of the NADPH-dependent alpha-KG reduction reaction.

More specifically, the biochemical reactions were performed at roomtemperature in 384-well Greiner flat-bottom plates (Costar, Cat. No.781201) using a final reaction volume of 30 μL and the following assaybuffer conditions: 50 mM HEPES pH 7.4, 10 mM MgCl₂, 50 mM KCl, 1 mM DTT,0.02% BSA, 5 uM NADPH and 100 uM alpha-KG.

The final reaction mixture contained 3.3% DMSO and inhibitors withconcentrations ranging 0.02-50 μM. The IDH1 enzyme was used at a finalconcentration of 0.25 nM. Following 45 minutes incubation, the reactionmixtures were quenched by the addition of 10 μL of 16% formic acidcontaining 800 nM of 5-carbon labeled ¹³C-2-HG). The protein was thenprecipitated by the addition of 2.5 volumes of acetonitrile followed bycentrifugation (3000×g, 20 minutes). The concentration of 2-HG in theresulting supernatants was measured by LC-MS (see below).

LC-MS method. Reaction mixture supernatants were submitted tochromatographic separation on a BiobasicAX column (2.1 mm×20 mm, 5 μmparticle, Thermo Scientific Inc.). The chromatographic mobile phaseswere A) 25 mM ammonium biocarbonate and B) acetonitrile (0.1% ammoniumhydroxide). Nicotinamide was eluted at 1 ml/min using a 85-5% B gradientover 0.9 minutes (Agilent 1200SL LC system, Thermofisher LX-4autosampler) and analyzed by multiple reaction monitoring (MRM) on aAPI4000 QTrap mass spectrometer (ABSciex, Framingham, Mass.) in thepositive electrospray ionization (ESI+) mode. The mass transition for2-HG and ¹³C-2-HG were 147→129 and 152→134, respectively. The relativeresponses (2-HG/¹³C-2-HG) were measured at varied inhibitorconcentrations and used to calculate inhibitory IC50 values (normalizedIC50 regression curves).

R132 Protein Expression and Purification.

IDH1 R132H was cloned into the pET47b vector using the restriction sitesXmaI/XhoI which yields an in frame, N-terminal His₆ site cleavable withPrescission protease. This plasmid was transformed into Rosetta™ 2(DE3)(Novagen) cells. In shake flasks, 8 L of cells were grown in TerrificBroth (Teknova) (plus kanamycin 50 μg/mL and chloramphenicol 34 μg/mL)at 37° C. to an OD₆₀₀ of 0.8 and protein expression was induced byaddition of IPTG to a concentration of 0.20 mM. The cells weresubsequently grown for 18 hours at 18° C.

His₆-IDH1 (R132H) Uncut protein (SEQ ID NO: 1)MAHHHHHHSAALEVLFQGPGMSKKISGGSVVEMQGDEMTRIIWELIKEKLIFPYVELDLHSYDLGIENRDATNDQVTKDAAEAIKKHNVGVKCATITPDEKRVEEFKLKQMWKSPNGTIRNILGGTVFREAIICKNIPRLVSGWVKPIIIGHHAYGDQYRATDFVVPGPGKVEITYTPSDGTQKVTYLVHNFEEGGGVAMGMYNQDKSIEDFAHSSFQMALSKGWPLYLSTKNTILKKYDGRFKDIFQEIYDKQYKSQFEAQKIWYEHRLIDDMVAQAMKSEGGFIWACKNYDGDVQSDSVAQGYGSLGMMTSVLVCPDGKTVEAEAAHGTVTRHYRMYQKGQETSTNPIASIFAWTRGLAHRAKLDNNKELAFFANALEEVSIETIEAGFMTKDLAACIKGLPNVQRSDYLNTFEFMDKLGENLKIKLAQAKL (stop)IDH1 (R132H) Prescission Cut Protein (N-term gpg is cloning artifact)(SEQ ID NO: 2) GPGMSKKISGGSVVEMQGDEMTRIIWELIKEKLIFPYVELDLHSYDLGIENRDATNDQVTKDAAEAIKKHNVGVKCATITPDEKRVEEFKLKQMWKSPNGTIRNILGGTVFREAIICKNIPRLVSGWVKPIIIGHHAYGDQYRATDFVVPGPGKVEITYTPSDGTQKVTYLVHNFEEGGGVAMGMYNQDKSIEDFAHSSFQMALSKGWPLYLSTKNTILKKYDGRFKDIFQEIYDKQYKSQFEAQKIWYEHRLIDDMVAQAMKSEGGFIWACKNYDGDVQSDSVAQGYGSLGMMTSVLVCPDGKTVEAEAAHGTVTRHYRMYQKGQETSTNPIASIFAWTRGLAHRAKLDNNKELAFFANALEEVSIETIEAGFMTKDLAACIKGLPNVQRSDYLNTFEFMDKLGENLKIKLAQAKL (stop)

Purification

The cells were homogenized in Lysis Buffer with protease inhibitors(cOmplete EDTA-free protease inhibitor tablets (Roche), 1 tablet per 50mL of buffer), DNAse, and to 200 μM PMSF and lysed in a Microfluidizer.After lysis, Triton X-100 was added to 0.1% and stirred at 4° C. for 30minutes.

The cleared lysate was loaded onto 2×5 mL HisTrap FF crude columns (GE),washed extensively with Lysis Buffer until the A₂₈₀ stabilized andeluted with Ni Elution Buffer. Peak eluted fractions were concentratedto 30 mL, EDTA was added to 1 mM and GST-Prescission protease was addedto 3 U/100 μg of protein. The sample was dialyzed against 2 L DialysisBuffer I (MWCO 50 kDa) for 6 hours at 4° C. then dialyzed against 2 L ofDialysis Buffer II for at least 6 more hours. GST-Prescission cleavedsample was rocked with Glutathione Agarose Beads, spun down and then thesupernatant was loaded through a 5 mL HisTrap HP column and the flowthrough was collected.

Flow through was then diluted with ice cold 20 mM Tris pH 7.4 and 1 mMTCEP until the conductivity dropped to less than 5 mS/cm (a roughlythree fold dilution). This sample was then flowed through a HiTrap Qcolumn and the flow through was concentrated to 10 mL and loaded onto anequilibrated 26/60 Superdex 200 column using SEC Buffer as the mobilephase. Peak fractions were collected, concentrated and aliquoted.

Lysis Buffer: 50 mM Tris pH=7.4, 500 mM NaCl, 20 mM Imidazole, and 1 mMTCEP

Ni Elution Buffer: 50 mM Tris pH=7.4, 150 mM NaCl, 200 mM Imidazole, and1 mM TCEP

Dialysis Buffer I: 20 mM Tris pH=7.4, 150 mM NaCl, 1 mM TCEP, and 50 mMImidazole

Dialysis Buffer II: 20 mM Tris pH=7.4, 150 mM NaCl, and 1 mM TCEP

SEC Buffer: 20 mM Tris pH=7.4, 150 mM NaCl, and 1 mM TCEP

The results of the mutant IDH1 biochemical assay (mIDH R132H) are givenin Table 40. Some of the examples were run in the assay multiple timesand therefore the IC₅₀ values are expressed as a range of activity.

Fluorescence Biochemical Assay

The IDH1 (R132H) mutant catalyzes the reduced form of NADP+ (NADPH) andα-ketoglutarate (α-KG) to form nicotinamide adenine dinucleotidephosphate (NADP+) and R(−)-2-hydroxyglutarate (2HG). The reaction can bemonitored kinetically by following the oxidation of NADPH to NADP+ whichis measured using fluorescence, excitation at 355 nm and emission at 530nm. Reactions were monitored using the Perkin-Elmer Envision, Model2101. More specifically, the biochemical reactions were performed atroom temperature in 384-well Greiner flat-bottom plates (Cat. No.781076) using a final reaction volume of 20 μL and the following assaybuffer conditions: 50 mM HEPES pH 7.5, 10 mM MgCl₂, 1 mM DTT, 0.02% BSA,0.02% Tween-20, 10 μM NADPH and 100 μM α-KG. The final reaction mixturecontained 2.5% DMSO and test compounds with concentrations ranging0.0000008-25 μM. The IDH1 (R132H) enzyme was used at a finalconcentration of 10 nM. Curve fitting for dose response IC50determinations was done using a 4-parameter logistic model:y=min+((max−min)/1+(x/IC₅₀)^(slope)).

The results of the fluorescence biochemical assay (mIDH R132H) are givenin Table 40. Some of the examples were run in the assay multiple timesand therefore the IC₅₀ values are expressed as a range of activity.

TABLE 40 Results of the LC-MS and fluorescence biochemical assays.Fluorescence LC-MS Example biochemical biochemical Number assay IC50(μM) assay IC₅₀ (μM) 1 1.410 Not determined 2 0.406 to 0.412 Notdetermined 3 Not determined Not determined 4 1.420 2.010 5 17.800 3.6846 1.270 1.185 7 2.950 1.609 to 4.527 8 2.040 0.314 to 2.79  9 2.2003.019 10 11.700 1.710 11 3.050 2.453 12 3.270 0.892 13 2.190 >5 14 0.4050.813 15 Not determined Not determined 16 Not determined Not determined17 Not determined Not determined 18 Not determined Not determined 19 Notdetermined Not determined 20 Not determined Not determined 21 Notdetermined Not determined 22 Not determined Not determined 23 Notdetermined Not determined 24 Not determined Not determined 25 Notdetermined Not determined 26 3.350 Not determined 27 2.800 Notdetermined 28 Not determined 0.005 29 Not determined 0.027 30 1.0900.472 31 0.627 0.757 32 0.016 0.010 33 3.660 2.085 34 0.889 to 0.8930.590 35 0.033 0.055 36 1.410 3.497 37 2.690 3.745 38 0.055 0.056 390.202 0.211 40 0.175 0.370 41 0.253 0.179 42 >25 1.557 43 Not determined0.045 44 0.029 0.033 to 0.034 45 1.000 1.237 46 2.530 1.930 47 0.0330.036 48 0.463 0.775 49 Not determined 0.094 50 0.037 0.043 51 0.0130.016 52 0.131 to 0.289 0.194 53 0.042 to 0.051 0.059 54 0.116 0.119 550.267 to 0.291 0.323 56 2.920 1.549 57 1.270 1.131 58 0.027 0.029 590.079 to 0.085 0.033 60 1.100 0.201 61 0.313 0.156 62  0.53 to 0.5990.087 63 <0.0159 0.005 64 <0.0159 0.008 65 0.797 0.582 66 0.061 to 0.0820.066 67 1.010 1.437 68 0.050 0.112 69 0.639 >5 70 0.073 0.080 71 >25 >572 Not determined 12.152 73 0.181 0.571 74 Not determined >5 75 Notdetermined Not determined 76 Not determined 0.546 to 0.568 77 Notdetermined 0.911 78 1.630 2.560 79 5.310 >5 80 0.037 0.031 81 Notdetermined 1.089 82 0.019 0.022 83 0.662 to 0.683 0.489 84 0.012 to0.083 0.013 85 1.930 0.524 86 0.032 to 0.049 0.019 87 6.690 >5 88 0.048to 0.058 0.034 89 1.360 1.776 90 0.034 0.013 91 0.274 Not determined 922.74 to 8.91 2.301 to 3.074 93 0.043 to 0.383 0.029 to 0.134 94 14.90025.642 95 1.530 1.113 96 Not determined >50 97 0.972 0.984 98 0.3510.487 99 9.790 3.057 100 Not determined 18.066 101 Not determined 0.572102 Not determined >50 103 Not determined 6.354 104 >25 >50 105 2.4301.720 106 >25 32.926 107 1.220 1.416 108 11.700 5.902 109 0.0486 to0.193  0.136 to 0.167 110 >25 23.402 111 2.780 3.511 112 >25 >50 113 >2542.325 114 >25 >50 115 7.890 3.760 116 >25 >50 117 1.410 2.010 118 3.5601.539 119 0.045 0.029 to 0.042 120 Not determined 2.668 121 0.182 0.045to 0.081 122 0.370 0.268 123 0.017 to 0.044 0.024 to 0.029 124 18.8 >25125 0.158 0.206 126 0.274 0.216 127 0.032 0.025 to 0.033 128 0.050 0.071129 1.800 2.814 130 1.510 2.999 131 0.056 0.153 to 0.171 132 0.956 1.421133 0.007 0.004 to 0.008 134 1.460 2.360 135 0.011 0.016 136 11.300 >5137 1.190 0.294 138 0.012 0.024 139 0.260 0.146 140 10.600 4.032 1410.660 0.116 142 >25 3.977 143 0.756 0.572 144 1.670 1.685 145 0.0200.036 146 Not determined >5 147 Not determined 0.368 148 9.590 >5 1490.194 0.168 to 0.216 150 Not determined >5 151 0.043 to 0.044 0.012 1525.990 >5 153 0.329 0.288 154 1.790 3.839 155 0.756 0.857 156 2.700 1.145157 0.033 0.032 158 Not determined 4.374 159 <0.0159 0.006 160 1.2301.115 161 0.158 0.305 162 3.620 >5 163 0.079 0.152 164 4.680 >5 1650.152 0.304 166 0.871 0.243 167 0.131 0.067 to 0.076 168 3.200 >5 1690.038 0.044 to 0.086 170 3.690 1.884 171 0.056 0.031 to 0.052 172 Notdetermined 3.407 173 0.051 to 0.078 0.040 174 0.230 0.238 175 0.298 to0.538 0.049 176 12.400 4.591 177 1.230 1.587 178 0.364 0.077 179 0.0070.005 to 0.006 180 >25 2.728 181 0.138 0.122 182 1.920 1.378 183 0.1280.243 184 0.502 0.757 185 0.023 0.021 186 2.32 to 2.58 2.583 187 0.0220.010 188 8.380 189 0.064 0.156 190 0.037 0.014 191 >50 192 Notdetermined 0.010 193 Not determined 0.358 194 0.051 Not determined 1952.930 Not determined 196 <0.0159 0.005 197 2.010 Not determined 1980.020 Not determined 199 1.200 Not determined 200 0.043 0.005 201 0.344Not determined 202 1.680 1.093 203 0.016 0.008 204 0.026 to 0.059 0.02to 0.05 205 2.700 2.052 206  0.03 to 0.051 0.022 207 as TFA salt 0.011<0.0228624 208 as TFA salt 0.101 Not determined 209 as TFA salt 0.0870.164 210 as TFA salt 0.153 0.374 211 as TFA salt 0.496 2.628 212 as TFAsalt 0.035 0.057 213 as TFA salt 0.011 <0.0228624 213 0.019 0.018 214 asTFA salt 0.046 0.107 215 as TFA salt 0.055 0.106 to 0.138 216 as TFAsalt 0.004 0.011 217 as TFA salt 0.012 to 0.033 0.019 to 0.025 218 asTFA salt 0.019 0.018 to 0.044 219 as TFA salt 0.014 0.015 220 as TFAsalt 0.014 0.017 221 0.061 0.046 222 as TFA salt 0.047 0.053 223 as TFAsalt 0.023 to 0.046 0.014 224 as TFA salt 0.029 0.027 224 <0.016 <0.022225 as TFA salt 0.037 0.063 225 0.028 to 0.042 0.038 to 0.043 226 as TFAsalt 0.009 Not determined 227 as TFA salt 0.015  0.22 to 0.023 228 asTFA salt 0.019 0.045 228 0.018 0.014 to 0.035 229 as TFA salt 0.0540.081 230 as TFA salt >25 Not determined 231 as TFA salt >25 Notdetermined 232 as TFA salt 0.024 0.026 233 as TFA salt 0.377 Notdetermined 234 as TFA salt 0.213 Not determined 235 as TFA salt 0.964Not determined 236 as TFA salt 0.024 to 0.042 0.023 237 as TFA salt 0.02 to 0.025 0.013 238 as TFA salt 0.017 to 0.024 0.012 239 as TFAsalt 0.049 to 0.058 0.020 240 as TFA salt 0.142 0.067 241 as TFA salt0.114 0.157 242 as TFA salt 0.042 0.053 243 as TFA salt 0.141 0.172 244as TFA salt 0.300 Not determined 245 as TFA salt 0.115 Not determined246 as TFA salt 0.273 Not determined 247 as TFA salt 0.079 Notdetermined 248 as TFA salt 0.172 Not determined 249 as TFA salt 0.635Not determined 250 as TFA salt 0.025 to 0.047 Not determined 251 as TFAsalt 0.020 Not determined 252 as TFA salt 0.309 0.353 to 0.482 253 asTFA salt 0.109 0.121 254 as TFA salt 0.234 Not determined 255 as TFAsalt 0.450 Not determined 256 as TFA salt 0.570 0.489 257 as TFA salt1.200 Not determined 258 as TFA salt 0.737 0.435 259 as TFA salt 0.1050.103 259 0.049 Not determined 260 as TFA salt 0.040 0.039 261 as TFAsalt 0.064 0.089 262 as TFA salt 0.088 0.167 263 as TFA salt 0.014 Notdetermined 264 as TFA salt 0.152 0.249 265 as TFA salt Not determined0.036 266 as TFA salt 0.453 Not determined 267 as TFA salt 0.048 0.095268 as TFA salt 0.338 Not determined 269 0.251 Not determined 270 as TFAsalt 0.174 0.163 271 as TFA salt 0.339 Not determined 272 as TFA salt0.117 Not determined 273 as TFA salt Not determined 0.585 274 as TFAsalt Not determined 0.265 275 as TFA salt Not determined 0.311 276 asTFA salt Not determined 0.051 277 as TFA salt Not determined 0.086 278as TFA salt 0.174 0.163 279 as TFA salt 12.700 Not determined 280 as TFAsalt 3.640 Not determined 281 as TFA salt 0.026 0.064 282 as TFA salt4.270 Not determined 283 as TFA salt 0.068 0.248 284 as TFA salt 0.266Not determined 285 as TFA salt 0.053 0.146 286 as TFA salt 0.036 0.145287 as TFA salt 2.250 46.301 288 as TFA salt 0.055 0.178 289 as TFA salt2.110 Not determined 290 as TFA salt 0.034 0.053 291 >25 Not determined292 1.850 Not determined 293 >7.91 Not determined 294 0.466 0.563295 >25 Not determined 296 0.251 0.277 297 2.960 Not determined 2980.020 0.038 299 0.457 Not determined 300 0.010 0.017 301 0.021 0.033 3020.045 Not determined 303 0.009 0.097 304 0.304 Not determined 305 0.9680.772 to 1.781 306 2.570 Not determined 307 as TFA salt 0.029 to 0.0490.038 308 as TFA salt 0.049 to 0.097 0.073 309 as TFA salt 0.003 0.004309 0.003 0.004 to 0.005 310 as TFA salt 0.072 0.128 311 as TFA salt0.518 0.445 312 as TFA salt 0.066 0.144 313 as TFA salt 0.020 0.019 314as TFA salt 0.106 to 0.121 0.157 to 0.182 315 as TFA salt 0.161 to 0.514 0.35 to 0.463 316 as TFA salt 0.123 to 0.29  0.261 317 as TFA salt  3.7to 5.63 Not determined 318 as TFA salt >25 Not determined 319 as TFAsalt 0.035 0.086 320 as TFA salt 0.426 0.381 321 as TFA salt 0.013 0.087322 as TFA salt 0.055 to 0.088 0.042 323 as TFA salt 0.071 to 0.1220.072 324 as TFA salt 0.030 Not determined 325 as TFA salt 0.041 0.181326 as TFA salt 0.063 Not determined 327 as TFA salt 0.236 0.562 328 asTFA salt 1.800 Not determined 329 as TFA salt 0.863 0.435 330 as TFAsalt 0.268 0.850 331 as TFA salt 0.190 0.780 332 as TFA salt 1.020 0.704333 as TFA salt 0.944 0.640 334 as TFA salt 0.341 0.943 335 as TFA salt0.257 0.166 to 0.167 336 as TFA salt 0.035 0.049 336 0.027 0.048 337 asTFA salt 0.313 0.119 338 as TFA salt 0.091 0.093 339 as TFA salt 0.0170.024 to 0.027 340 as TFA salt 0.061 0.120 341 as TFA salt 7.050 Notdetermined 342 as TFA salt 0.465 4.001 343 as TFA salt 0.073 0.225 344as TFA salt 0.190 0.300 345 as TFA salt 0.201 0.378 346 as TFA salt0.189 0.290 347 as TFA salt 0.395 0.564 348 as TFA salt 0.177 0.128 349as TFA salt 0.681 Not determined 350 as TFA salt 0.413 Not determined351 as TFA salt 0.168 Not determined 352 as TFA salt 0.770 Notdetermined 353 as TFA salt 0.103 0.117 354 as TFA salt 0.051 0.286 355as TFA salt 0.152 0.381 356 as TFA salt 0.120 0.132 357 as TFA salt0.358 0.439 358 as TFA salt 0.123 Not determined 359 as TFA salt 0.1710.193 360 as TFA salt 0.056 0.119 361 as TFA salt 0.107 0.170 362 as TFAsalt 0.072 0.142 363 as TFA salt 0.007 0.009 364 as TFA salt 0.124 0.286to 0.472 365 as TFA salt 0.033 0.137 366 as TFA salt 0.151 0.345 367 asTFA salt 0.127 0.209 368 as TFA salt 0.091 0.127 369 as TFA salt 0.3971.277 370 as TFA salt 0.441 1.303 371 as TFA salt 0.125 0.110 372 as TFAsalt 0.014 to 0.044 0.029 373 as TFA salt 0.051 Not determined 374 0.0320.021 375 0.093 0.241 376 as TFA salt 0.023 0.027 377 as TFA salt 0.052Not determined 378 as TFA salt 0.025 to 0.028 Not determined 379 as TFAsalt 0.053 Not determined 380 as TFA salt 0.036 to 0.037 0.050 380 0.036to 0.055 Not determined 381 as TFA salt 0.139 0.059 382 as TFA salt0.219 0.098 383 as TFA salt 0.164 Not determined 384 as TFA salt 10.5to >25  Not determined 385 as TFA salt 0.017 <0.023 385 <0.016 to 0.027 0.007 386 as TFA salt 0.059 Not determined 387 as TFA salt 0.032 to0.036 Not determined 388 as TFA salt <0.0159 0.006 389 as TFA salt 0.020Not determined 390 as TFA salt 0.022 to 0.037 0.022 391 as TFA salt0.038 to 0.067 Not determined 392 as TFA salt 0.101 to 0.142 Notdetermined 393 as TFA salt 0.057 to 0.081 Not determined 394 as TFA salt0.037 to 0.046 Not determined 395 as TFA salt 0.034 to 0.045 Notdetermined 396 as TFA salt 0.024 to 0.041 Not determined 397 as TFA salt0.064 to 0.067 Not determined 398 as TFA salt 0.038 to 0.04  Notdetermined 399 as TFA salt 0.018 Not determined 400 as TFA salt 0.018 to0.033 Not determined 401 as TFA salt 0.023 to 0.03  Not determined 4010.018 Not determined 402 as TFA salt 0.044 to 0.05  Not determined 403as TFA salt 0.137 Not determined 404 0.021 to 0.025 Not determined 4050.027 to 0.037 Not determined 406 as TFA salt 0.028 to 0.03  Notdetermined 407 0.071 Not determined 408 0.043 Not determined 409 as TFAsalt 0.209 0.501 to 0.515 410 as TFA salt 0.020 0.034 411 as TFA salt0.756 1.601 412 as TFA salt 0.108 0.223 to 0.347 413 as TFA salt 0.023Not determined 414 as TFA salt 2.210 Not determined 415 0.483 to 0.8590.204 416 0.097 0.110 417 0.207 0.078 to 0.147 418 0.015 to 0.044 0.016to 0.075 419 0.096 0.039 to 0.06  420 0.089 0.047 to 0.078 421 0.0230.021 422 1.76 to 2.03 Not determined 423 0.036 to 0.042 Not determined424 7.710 6.429 425 0.303 0.202 to 0.214 426 as TFA salt <0.0159 Notdetermined 427 as TFA salt 0.039 to 0.55  Not determined 428 as TFA salt0.0678 Not determined 429 <0.016 Not determined 430 as TFA salt 0.050Not determined 431 as TFA salt 0.047 Not determined 432 as TFA salt0.016 Not determined 433 as TFA salt 0.032 Not determined 434 as TFAsalt 0.017 Not determined 435 as TFA salt 0.017 Not determined 436 asTFA salt 0.06 Not determined 437 as TFA salt 0.036 Not determined 438 asTFA salt 0.045 Not determined 439 as TFA salt 0.392 Not determined 440as TFA salt 0.172 Not determined 441 as TFA salt <0.016 Not determined442 as TFA salt 0.038 Not determined 443 as TFA salt 0.029 Notdetermined 444 as TFA salt <0.016 Not determined 445 as TFA salt 0.112Not determined 446 as TFA salt 0.0268 Not determined 447 as TFA salt0.028 Not determined 448 as TFA salt <0.016 Not determined 449 as TFAsalt 0.0297 Not determined 450 as TFA salt <0.016 Not determined 451 asTFA salt 0.0435 Not determined 452 as TFA salt 0.0293 Not determined 453as TFA salt 0.0357 Not determined 454 as TFA salt 0.0234 Not determined455 as TFA salt <0.016 Not determined 456 as TFA salt <0.016 Notdetermined 456 0.0010 Not determined 457 as TFA salt 0.017 Notdetermined 458 as TFA salt <0.016 Not determined 459 as TFA salt 0.0246Not determined 460 as TFA salt 0.024 to 0.043 Not determined 461 as TFAsalt 0.045 to 0.064 Not determined 462 as TFA salt 0.0738 Not determined463 as TFA salt 0.038 0.010 463 0.035 to 0.040 0.039 464 as TFA salt0.0937 Not determined 465 as TFA salt 0.0681 Not determined 466 0.024 to0.027 0.011 467 0.008 to 0.010 <0.00229 468 0.128 0.023 469 0.020 Notdetermined 470 Not determined 0.0128 471 as TFA salt 0.049 Notdetermined 472 as TFA salt 0.032 Not determined 473 as TFA salt 0.019Not determined 474 as TFA salt 0.077 Not determined 475 as TFA salt0.022 Not determined 476 as TFA salt 0.012 Not determined 477 0.017 Notdetermined 478 as TFA salt 0.051 Not determined 479 as TFA salt. 0.087Not determined 480 0.014-0.020 0.005

IDH Cellular Assay

The IDH cellular assay consisted of two side-by-side comparatorassays: 1) 2HG oncometabolite detection assay using LC-MS (See MutantIDH1 biochemical assay for LC-MS detection details) and 2) Cellproliferation assay to monitor off-target killing of cells and tonormalize 2HG level change.

IDH1 cellular screens were run with the HCT-116 cell line (expressendogenous level of IDH1mut R132H, available from Horizon DiscoveriesX-Man isogenic human cell lines, catalog # HD104-013). The cells weregrown in DMEM (LONZA Cat#12-540F) with 10% Fetal bovine serum (Gibcocat#10099) and 1× non-essential amino acids (NEAA LONZA cat#13-114E).Panel assays were run periodically to test compound activity in celllines with different endogenous mutations—HT1080 (IDH1mut R132C,EMEM+10% FBS), SNU-1079 (IDH1mut R132C, RPMI+10% FBS+1% sodiumpyruvate), and SW1353 (IDH2mut R172S, RPMI+10% FBS+1% sodium pyruvate).

The assay process was as follows:

Day 1: cells were seeded in 384-well plates (Corning Cat#3707) intriplicates for both the cell proliferation and 2HG assay, and incubatedat 37 C, 95% Rh, 5% CO2 overnight.

Day 2: compounds were serially diluted 1:3 (10 point dilution from 10 mMsolutions in DMSO) and delivered to the cell assay plates via acousticdispenser, with final concentration ranging from 30 uM to 1.5 nM. Theplates were returned to the incubator after treatment and incubated for48 hours.

Day 4 Proliferation assay: CTG (cell titer-glo, Promega part # G755B)was added to the assay plates and luminescence signal was read on theplate reader.

Day 4 2HG assay: Extraction sample preparation consisted of aspiratingall media from the assay plates, adding 70 ul of 90% methanol in water,dry ice incubation for 15 minutes, centrifuging at 2000 rpm for 30 minto ensure all particulates have settled, and transferring 30 ul of thesupernatant into LC-MS ready plates. LC-MS analysis followed.

Certain compounds of the invention were tested in the IDH CellularAssay.

Determination of Metabolic Stability in Liver Microsomes—Method I

The in vitro metabolic stability assay was performed in a 96-well glassplate with shaking incubation at 37° C. A 10 mM DMSO stock solution ofthe test compound was sequentially diluted 1:1000 to yield a finalreaction concentration of 1 μM in 50 mM KPi. Immediately prior to thestart of the experiment, respective animal or human liver microsomes(male Sprague-dawley rat, male CD-1 mouse, or pooled human livermicrosomes) were diluted in 50 mM KPi to 1.25 mg/mL liver microsomalprotein. 30 μL of the 10 μM solution containing the test compound wasadded to 120 μL of microsomal protein for 150 μL enzyme-compoundmixture. The reaction was initiated by adding 150 μL of cofactorsolution (2 mM NADPH, 4 mM MgCl in 50 mM KPi) to the enzyme-compoundmixture, and the final reaction concentrations are listed in the tablebelow.

Final Reaction Concentrations Reaction component Final reactionconcentration Potassium phosphate (KPi) buffer, pH 7.4 50 mM MgCl₂ 2.0mM NADPH 1.0 mM Liver microsomes 0.5 mg/mL Test compound 1.0 μM DMSO(test compound solvent) 0.01% (v/v)

At 0, 5, 10 and 30 minute time points in the reaction, reaction aliquots(50 μL) were removed and the reactions were terminated by the additionof acetonitrile (150 μL) containing a mass spectrometry internalstandard (1 μM glyburide). The samples were centrifuged and thesupernatants analyzed by LC-MS/MS for quantization of remainingcompound. The percentage of compound remaining, relative to 0 minutes,was used to estimate in vitro elimination-rate constant (k_(mic)) whichwas used to calculate in vitro metabolic clearance rates.

Analysis of the samples was performed on a high performance liquidchromatography-tandem mass spectrometry (LC/MS) system consisting of aThermo TSQ Quantum Ultra mass spectrometer, an H-ESI ion source, aCTC-HTS Pal autosampler, and an Agilent LC Pump. Samples were separatedon an XTerra C18 column, 2.1×20 mm, 3.5 μm using the fast mobile phasegradient outlined below.

Time (min) % B 0.0 5 0.2 5 0.85 95 1.02 95 1.05 5Mobile phase A consisted of purified water containing 0.01% formic acid.Mobile phase B consisted of acetonitrile containing 0.01% formic acid.The flow rate was 1 mL/min. The injection volume was 10 μL. Compoundswere detected using the Thermo QuikQuan software which collectsintensity data for all fragments related to the molecular weight of thetest compound. After collection of the raw data, the software identifiesand integrates the peak of the strongest intensity.

Each microsomal elimination rate, k_(mic), was based on a 4-pointelimination curve tested in singlet. LC-MS/MS raw data for a reactionplate was returned as integrated analyte peak areas for the testcompound and internal standard used in the quench solution for thereaction to enable use of analyte:internal standard peak area ratios(PARs) for all data comparisons. The reaction time point (e.g. 0, 5, 20or 30 minutes) was plotted versus the natural logarithm of percent testcompound remaining relative to 0 minutes (based on relative PAR). Theslope of this clearance plot, k_(mic), was used to calculate the invitro half-life, t_(1/2), In order to focus on linear reaction kinetics,whenever possible, data points representing <10% test compound remainingwere generally omitted from the definition of the clearance plot slope.

Determination of Metabolic Stability in Liver Microsomes—Method II

The in vitro metabolic stability assay was performed in a 96-deep-wellplate with incubation at 37° C. 10 mM DMSO stock solution of the testcompound was diluted 1:20 in acetonitrile, followed by an additional1:10 dilution in 100 mM potassium phosphate buffer (KPi) to yield afinal reaction concentration of 1 μM. Immediately prior to the start ofthe experiment, respective animal or human liver microsomes (maleSprague-dawley rat, male CD-1 mouse, or pooled human liver microsomes)were diluted in 100 mM KPi to 1.25 mg/mL liver microsomal protein. 290μL of cofactor solution (1.7 mM NADPH, 1.7 mM UDPGA, 3.4 mM MgCl in 100mM KPi) was added to 200 μL of microsomal protein for a final volume of490 μL. The reaction was initiated by adding 10 μL of the 50 μM testsolution to 490 μL of microsomal protein for a final volume 500 μLenzyme-compound mixture.

The final reaction concentrations are listed in the table below:

Final Reaction Concentrations Reaction component Final reactionconcentration Potassium phosphate (KPi) buffer, pH 7.4 50 mM MgCl₂ 2.0mM NADPH 1.0 mM UDPGA 1.0 mM Liver microsomes 0.5 mg/mL Test compound1.0 μM DMSO (test compound solvent) 0.01% (v/v)

At 0, 5, 15 and 30 minute time points in the reaction, reaction aliquots(75 μL) were removed and the reactions were terminated by the additionof 50:50 acetonitrile/methanol solution (75 μL) containing a massspectrometry internal standard (0.5 μM glyburide). The samples werecentrifuged at 4000 RPM for 10 minutes. Supernatants (15 μL aliquots)were transferred to a new plate where each well contains 90 μL ofdeionized water. The supernatants solution were analyzed by UPLC/MS/MSfor quantitation of parent remaining compound under multiple reactionsmonitoring mode (MRM) in positive mode. The percentage of compoundremaining, relative to 0 minutes, was used to estimate in vitroelimination-rate constant (k) which was used to calculate in vitrometabolic clearance rates.

Analysis of the samples was performed on an ultra-performance liquidchromatography-tandem mass spectrometry (UPLC/MS/MS) system consistingof an AB Sciex Qtrap 5500 mass spectrometer, AB Sciex Turbo V ionsource, Waters Acquity Sample Organizer, Waters Acquity Column manager,Waters Acquity Sample manager, and a Waters Acquity Binary SolventManager. Chromatographic separation of analyte and internal standard wasachieved using a reverse phase C-18 column (50×2.1 mm, 1.7 μm, AcquityUPLC BEH C-18) with the following UPLC mobile phases and elutiongradient:

UPLC mobile phase A: 0.25% formic acid in 5% methanol; mobile phase B:0.25% formic acid in 95% water.LC gradient and flow rate are listed below:

 0-.01 min 10% B 700 μL/min 0.01-1.0 min  10-95% B    700 μL/min 1.0-1.1min 95% B 700 μL/min 1.1-1.2 min 95-10% B    700 μL/min 1.2-1.5 min 10%B 700 μL/minThe injection volume was 5 μL. Compounds were detected using Analyst1.5.1 software which collects intensity data for all fragments relatedto the molecular weight of the test compound. After collection of theraw data, the software identifies and integrates the peak of thestrongest intensity.

Each microsomal elimination rate, k, was based on a 4-point eliminationcurve tested in duplicates. LC-MS/MS raw data for a reaction plate wasreturned as integrated analyte peak areas for the test compound andinternal standard used in the quench solution for the reaction to enableuse of analyte:internal standard peak area ratios (PARs) for all datacomparisons. The reaction time point (e.g. 0, 5, 15 and 30 minutes) wasplotted versus the natural logarithm of percent test compound remainingrelative to 0 minutes (based on relative PAR). The slope of thisclearance plot, k, was used to calculate the in vitro half-life.

${{Half}\mspace{14mu} {{life}( t_{1/2} )}( \min )} = \frac{- 0.693}{k}$

The intrinsic clearance value, CL_(int) (expressed as μL/min/mgmicrosomal protein) calculation is shown below:

${CL}_{int} = {\frac{0.693}{t_{1/2}} \cdot \frac{V}{M}}$

Where V=the incubation volume (mL) and M=the microsomal protein contentin the incubation (mg)

TABLE 41 Results of the metabolic stability assays Rat Mouse HumanExample microsomal stability microsomal stability microsomal stabilityNumber CL_(int) [μl min−1 mg−1] CL_(int) [μl min−1 mg−1] CL_(int) [μlmin−1 mg−1] Method  48 49.09 173.08  120.53  I  55 58.41 63.12 Notdetermined I  61 34.65 67.65 66.43 I 122 69.39 Not determined Notdetermined I 169 68.78 Not determined Not determined I 60.93 174 48.53Not determined Not determined I 175 50.51 56.29 39.77 I 181 56.58 Notdetermined Not determined I 380 42.93 I 30.16 51.00 31.15 II 401 30.38 I92.37 33.13 <7.70 II 404 44.6 I 75.44 18.72 <7.70 II 434 as TFA salt40.97 I 10.81 10.68 <7.70 II 456 as TFA salt 44.66 I 72.50 63.03 16.79II 463 50.8 I 49.78 35.45 28.27 II 466 44.90 57.89 55.93 I 467 75.56 I85.38 274.97  53.27 II 468 30.46 28.95 70.11 I 469 131.74 Not determinedNot determined I 470 52.76 47.31 83.59 I 471 as TFA salt <7.70 14.75<7.70 II 472 as TFA salt 12.03 45.59 <7.70 II 473 as TFA salt 72.47 I33.29 17.66 <7.70 II 474 as TFA salt 24.78 <7.70 <7.70 II 475 as TFAsalt 53.95 I 16.24 15.72 <7.70 II 476 as TFA salt 344.08 110.74  41.35II 477 437.89 167.04  30.44 II 478 as TFA salt 219.31 55.30 10.94 II 479as TFA salt 172.65 116.32  11.86 II 480 65.24 51.46 35.57 I

Enumerated Embodiments Embodiment 1

A compound according to formula (I)

wherein:R¹ is hydrogen, methyl or ethyl;R^(2a) is hydrogen, methyl or C₁₋₃ haloalkyl;R^(2b) is OH, halo, C₁₋₆ alkoxy, C₁₋₃ haloalkyl, NH₂, NH(CH₃) orN(CH₃)₂;R³ and R⁴ are each independently hydrogen, methyl or ethyl or R³ and R⁴are joined together forming cyclopropyl, cyclobutyl or oxetanyl;R⁵ and R⁶ are each independently hydrogen, deuterium, halo, —C(O)OCH₃,C₁₋₃ alkyl or C₁₋₃ haloalkyl;

R⁷ is

wherein:

-   -   ring A is a 6 membered heteroaryl ring having one to three        nitrogen atoms;    -   ring B is a 5 membered heteroaryl ring having one to four        heteroatoms each independently selected from the group        consisting of N, O and S;    -   X is N or CH;

each R⁸ is independently hydrogen, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl,C₁₋₃ alkoxy or C₁₋₃ haloalkoxy;

-   -   n is 1 or 2;    -   R⁹ is hydrogen, halo, C₁₋₃ haloalkyl, optionally substituted        C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl, optionally        substituted aryl, optionally substituted 5 or 6 membered        heterocyclic, optionally substituted heteroaryl, —OR^(9a),        —SO₂R^(9a), —C(O)NHR^(9a), CH₂R^(9b) or CHCH₃R^(9b), provided        that when X is N, R⁹ is hydrogen, C₁₋₃ haloalkyl, optionally        substituted C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl,        optionally substituted aryl, optionally substituted heteroaryl,        —SO₂R^(9a) or —C(O)NHR^(9a), wherein:        -   said C₁₋₆ alkyl is optionally substituted with one to three            substituents each independently selected from the group            consisting of: OH, phenyl and phenoxy, and        -   said C₃₋₆ cycloalkyl, 5 or 6 membered heterocyclic, aryl and            heteroaryl are each optionally substituted with one to three            substituents each independently selected from the group            consisting of: halo, hydroxyl, cyano, —NRR, C₁₋₆ alkyl, C₁₋₆            haloalkyl, C₁₋₃ alkoxy, and C₁₋₃ haloalkoxy;    -   R^(9a) is optionally substituted C₁₋₆ alkyl, C₁₋₆ haloalkyl,        optionally substituted C₃₋₆ cycloalkyl, optionally substituted        phenyl, or optionally substituted heterocyclic,    -   wherein:        -   said C₁₋₆ alkyl is optionally substituted with one C₃₋₆            cycloalkyl,        -   said C₃₋₆ cycloalkyl and heterocyclic are each optionally            substituted with one to three substituents each            independently selected from the group consisting of:            hydroxyl, CH₂OH, —NRR, cyano, C₁₋₃ alkyl, C₁₋₃ haloalkyl,            and C₁₋₃ alkoxy, and        -   said phenyl is optionally substituted with one to three            substituents each independently selected from the group            consisting of: halo, hydroxyl, cyano, —NRR, C₁₋₆ alkyl, C₁₋₆            haloalkyl, C₁₋₃ alkoxy, and C₁₋₃ haloalkoxy;    -   R^(9b) is optionally substituted C₃₋₆ cycloalkyl, optionally        substituted phenyl or optionally substituted heterocyclic,        -   said C₃₋₆ cycloalkyl and heterocyclic are each optionally            substituted with one to four substituents each independently            selected from the group consisting of: hydroxyl, CH₂OH,            —NRR, —NRC(O)CH₃, 4 to 6 membered heterocyclic, cyano, halo,            C₁₋₃ alkyl, C₁₋₃ haloalkyl, and C₁₋₃ alkoxy, and        -   said phenyl is optionally substituted with one to three            substituents each independently selected from the group            consisting of: halo, hydroxyl, cyano, C₁₋₆ alkyl, C₁₋₆            haloalkyl, C₁₋₃ alkoxy, and C₁₋₃ haloalkoxy; and

each R is independently selected from the group consisting of H, C₁₋₃alkyl and C₃₋₆ cycloalkyl; or a pharmaceutically acceptable saltthereof.

Embodiment 2

The compound according to embodiment 1 wherein R³ and R⁴ are bothhydrogen; or a pharmaceutically acceptable salt thereof.

Embodiment 3

The compound according to embodiment 1 or 2 wherein R¹ is hydrogen; or apharmaceutically acceptable salt thereof.

Embodiment 4

The compound according to any one of embodiments 1-3 according toformula (II):

or a pharmaceutically acceptable salt thereof.

Embodiment 5

The compound according to any one of embodiments 1-4 wherein:

-   -   R⁵ is hydrogen or halo; and    -   R⁶ is hydrogen, halo, methyl, CH₂F, CHF₂, or CF₃; or a        pharmaceutically acceptable salt thereof.

Embodiment 6

The compound according to embodiment 5 wherein R⁵ is hydrogen; or apharmaceutically acceptable salt thereof.

Embodiment 7

The compound according embodiment 5 wherein R⁶ is hydrogen; or apharmaceutically acceptable salt thereof.

Embodiment 8

The compound according to embodiment 5 wherein R⁵ and R⁶ are bothhydrogen; or a pharmaceutically acceptable salt thereof.

Embodiment 9

The compound according to any one of embodiments 1-8 wherein R^(2a) ismethyl; or a pharmaceutically acceptable salt thereof.

Embodiment 10

The compound according to any one of embodiments 1-9 wherein R^(2b) isOH, fluoro, methoxy, t-butoxy, CHF₂, CF₃, NH₂ or NH(CH₃); or apharmaceutically acceptable salt thereof.

Embodiment 11

The compound according to any one of embodiments 1-10 having thefollowing formula:

wherein R^(2b) is OH, NH₂ or fluoro; or a pharmaceutically acceptablesalt thereof.

Embodiment 12

The compound according to any one of embodiments 1-11 according toformula (IV):

wherein R^(2b) is OH or NH₂; or a pharmaceutically acceptable saltthereof.

Embodiment 13

The compound according to embodiment 12 wherein R^(2b) is OH; or apharmaceutically acceptable salt thereof.

Embodiment 14

The compound according to embodiment 12 wherein R^(2b) is NH₂; or apharmaceutically acceptable salt thereof.

Embodiment 15

The compound according to any one of embodiments 1-11 according toformula (V):

or a pharmaceutically acceptable salt thereof.

Embodiment 16

The compound according to embodiment 15 wherein R^(2a) is methyl; or apharmaceutically acceptable salt thereof.

Embodiment 17

The compound according to any one of embodiments 1-16 wherein R⁷ is:

or a pharmaceutically acceptable salt thereof.

Embodiment 18

The compound according to any one of embodiments 1-17 wherein R⁹ ishydrogen, halo, C₁₋₃ haloalkyl, optionally substituted C₁₋₆ alkyl oroptionally substituted C₃₋₆ cycloalkyl; or a pharmaceutically acceptablesalt thereof.

Embodiment 19

The compound according to any one of embodiments 1-17 wherein R⁹ isphenyl optionally substituted with one or two substituents eachindependently selected from the group consisting of: fluoro, chloro,bromo, cyano, methoxy, CH₂OH, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₃haloalkoxy; or a pharmaceutically acceptable salt thereof.

Embodiment 20

The compound according to any one of embodiments 1-17 wherein R⁹ ispyrazolyl, pyridinyl, indolyl or isoquinolinyl each of which isoptionally substituted; or a pharmaceutically acceptable salt thereof.

Embodiment 21

The compound according to any one of embodiments 1-17 wherein R⁹ isCH₂R^(9b) wherein R^(9b) is piperidinyl, piperazinyl or morpholinyl eachof which is optionally substituted with one to three substituents eachindependently selected from the group consisting of: hydroxyl, halo,CH₂OH, —NRR, cyano, C₁₋₃ alkyl, C₁₋₃ haloalkyl, and C₁₋₃ alkoxy.

Embodiment 22

The compound according to embodiment 1 according to formula (IV)

wherein:

R^(2b) is OH;

R⁵ is hydrogen or fluoro;

R⁶ is hydrogen, chloro, methyl or CH₂F;

R⁷ is

R⁸ is hydrogen, methyl or fluoro;n is 1 or 2; and

R⁹ is methylcyclopropyl, isobutoxy, phenyl optionally substituted withone or two substituents each independently selected from the groupconsisting of: fluoro, chloro, bromo, C₁₋₄ alkyl, CF₂H and CF₃ orpyridinyl optionally substituted with one or two substituents eachindependently selected from the group consisting of: methyl, CF₃ andC(CH₃)₂CF₃; or a pharmaceutically acceptable salt thereof.

Embodiment 23

The compound according to embodiment 22 wherein:

R⁵ is hydrogen and R⁶ is chloro, methyl or CH₂ForR⁶ is hydrogen and R⁵ is fluoro; or a pharmaceutically acceptable saltthereof.

Embodiment 24

The compound according to embodiment 22 wherein R⁵ and R⁶ are bothhydrogen; or a pharmaceutically acceptable salt thereof.

Embodiment 25

The compound according to embodiment 1 according to formula (VI)

wherein:R^(2b) is fluoro;R⁵ is hydrogen or fluoro;R⁶ is hydrogen;

R⁷ is

R⁸ is hydrogen or methyl;n is 1; andR⁹ is phenyl optionally substituted with one chloro; or apharmaceutically acceptable salt thereof.

Embodiment 26

The compound according to embodiment 1 selected from the groupconsisting of:

-   (R)-4-((R)-1-hydroxy(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-onethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(6-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-chloro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-chloro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(3-chloro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (4R)-3-(5-fluoro-2-(((S)-1-(4-methyl-5-(2-(1,    1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;    and-   (R)-3-(2-(((S)-1-(2,5-difluoro-4-(2-methylpyridin-4-yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;    or a pharmaceutically acceptable salt thereof.

Embodiment 27

The compound according to embodiment 1 selected from the groupconsisting of:

-   (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-{2-[((R)1-(3-(3-fluoro-4-methylphenyl)-1,2,4-oxadiazol-5-yl)ethyl]amino}pyrimidin-4-yl}-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;-   (R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-5-fluoro-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one;-   (R)-3-(5-fluoro-2-(((S)-1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(4-(4-bromophenyl)thiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-(fluoromethyl)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(2-(4-(difluoromethyl)phenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;-   (R)-3-(6-chloro-2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;    and-   (R)-3-(2-(((S)-1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;    or a pharmaceutically acceptable salt thereof.

Embodiment 28

The compound according to embodiment 1 selected from the groupconsisting of:

-   (R)-3-(2-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)    oxazolidin-2-one;-   (R)-3-(5-fluoro-2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;    and-   (R)-3-(2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one;    or a pharmaceutically acceptable salt thereof.

Embodiment 29

The compound according to embodiment 1 selected from the groupconsisting of:

-   (R)-3-(6-chloro-2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)    amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl) oxazolidin-2-one; and-   (S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;    or a pharmaceutically acceptable salt thereof.

Embodiment 30

The compound according to embodiment 1 selected from the groupconsisting of:

-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)    amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl) oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(2-(4-chlorophenyl) thiazol-5-yl)ethyl)amino)    pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(5-(4-chlorophenyl) isoxazol-3-yl)ethyl)amino)    pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)    amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-fluoroethyl)    oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-2-methyl-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)    oxazolidin-2-one;-   (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)    amino)pyrimidin-4-yl)oxazolidin-2-one;-   (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one;    and-   (S)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one;    or a pharmaceutically acceptable salt thereof.

Embodiment 31

The compound according to embodiment 1 which is(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-oneor a pharmaceutically acceptable salt thereof.

Embodiment 32

The compound according to embodiment 1 which is(S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-oneor a pharmaceutically acceptable salt thereof.

Embodiment 33

The compound according to embodiment 1 which is(R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one or a pharmaceutically acceptablesalt.

Embodiment 34

The compound according to embodiment 1 which is(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-oneor a pharmaceutically acceptable salt thereof.

Embodiment 35

The compound according to embodiment 1 which is(R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-oneor a pharmaceutically acceptable salt thereof.

Embodiment 36

The compound according to embodiment 1 which is(R)-3-(5-fluoro-2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-oneor a pharmaceutically acceptable salt thereof.

Embodiment 37

The compound according to embodiment 1 which is(R)-3-(2-(((S)-1-(1-(3-chloro-4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-oneor a pharmaceutically acceptable salt thereof.

Embodiment 38

A pharmaceutical composition comprising a compound according to any oneof embodiments 1-37, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier or excipient.

Embodiment 39

A method for the treatment of a disease or disorder associated with amutant IDH protein having a neomorphic activity comprisingadministration of a therapeutically effective amount of a compoundaccording to any one of embodiments 1-37, or a pharmaceuticallyacceptable salt thereof, to subject in need of treatment thereof.

Embodiment 40

A method for the treatment of a disease or disorder associated with amutant IDH protein having a neomorphic activity comprisingadministration of a therapeutically effective amount of a compoundaccording to any one of embodiments 1-37, or a pharmaceuticallyacceptable salt thereof, and another therapeutic agent to a subject inneed of treatment thereof.

Embodiment 41

A method for the treatment of brain cancer, leukemia, skin cancer,prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcomacomprising administration of a compound according to any one of previousembodiments 1-37, or a pharmaceutically acceptable salt thereof, to asubject in need of treatment thereof.

Embodiment 42

A method for the treatment of glioma, glioblastoma multiforme,paraganglioma, suprantentorial primordial neuroectodermal tumors, acutemyeloid leukemia, myelodysplastic syndrome, chronic myelogenousleukemia, melanoma, prostate, thyroid, colon, lung, centralchondrosarcoma, central or periosteal chondroma tumors, fibrosarcoma, orcholangiocarcinoma comprising administration of a compound according toany one of previous embodiments 1-37, or a pharmaceutically acceptablesalt thereof, to a subject in need of treatment thereof.

Embodiment 43

A compound according to any one of previous embodiments 1-37, or apharmaceutically acceptable salt thereof, for use in the treatment ofbrain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer,colon cancer, lung cancer or sarcoma.

Embodiment 44

A compound according to any one of previous embodiments 1-37, or apharmaceutically acceptable salt thereof, for use in the treatment ofglioma, glioblastoma multiforme, paraganglioma, suprantentorialprimordial neuroectodermal tumors, acute myeloid leukemia,myelodysplastic syndrome, chronic myelogenous leukemia, melanoma,prostate, thyroid, colon, lung, central chondrosarcoma, central orperiosteal chondroma tumors, fibrosarcoma, or cholangiocarcinoma.

Embodiment 45

A compound according to embodiment 1 which is(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-oneor a pharmaceutically acceptable salt thereof.

1. A compound according to formula (I)

wherein: R¹ is hydrogen, methyl or ethyl; R^(2a) is hydrogen, methyl orC₁₋₃ haloalkyl; R^(2b) is OH, halo, C₁₋₆ alkoxy, C₁₋₃ haloalkyl, NH₂,NH(CH₃) or N(CH₃)₂; R³ and R⁴ are each independently hydrogen, methyl orethyl or R³ and R⁴ are joined together forming cyclopropyl, cyclobutylor oxetanyl; R⁵ and R⁶ are each independently hydrogen, deuterium, halo,—C(O)OCH₃, C₁₋₃ alkyl or C₁₋₃ haloalkyl; R⁷ is

wherein: ring A is a 6 membered heteroaryl ring having one to threenitrogen atoms; ring B is a 5 membered heteroaryl ring having one tofour heteroatoms each independently selected from the group consistingof N, O and S; X is N or CH; each R⁸ is independently hydrogen, halo,C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy or C₁₋₃ haloalkoxy; n is 1 or 2;R⁹ is hydrogen, halo, C₁₋₃ haloalkyl, optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₆ cycloalkyl, optionally substituted aryl,optionally substituted 5 or 6 membered heterocyclic, optionallysubstituted heteroaryl, —OR^(9a), —SO₂R^(9a),

C(O)NHR^(9a), CH₂R^(9b) or CHCH₃R^(9b), provided that when X is N, R⁹ ishydrogen, C₁₋₃ haloalkyl, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₆ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, —SO₂R^(9a) or —C(O)NHR^(9a), wherein: said C₁₋₆alkyl is optionally substituted with one to three substituents eachindependently selected from the group consisting of: OH, phenyl andphenoxy, and said C₃₋₆ cycloalkyl, 5 or 6 membered heterocyclic, aryland heteroaryl are each optionally substituted with one to threesubstituents each independently selected from the group consisting of:halo, hydroxyl, cyano,

NRR, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₃ alkoxy, and C₁₋₃ haloalkoxy;R^(9a) is optionally substituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, optionallysubstituted C₃₋₆ cycloalkyl, optionally substituted phenyl, oroptionally substituted heterocyclic, wherein: said C₁₋₆ alkyl isoptionally substituted with one C₃₋₆ cycloalkyl, said C₃₋₆ cycloalkyland heterocyclic are each optionally substituted with one to threesubstituents each independently selected from the group consisting of:hydroxyl, CH₂OH, —NRR, cyano, C₁₋₃ alkyl, C₁₋₃ haloalkyl, and C₁₋₃alkoxy, and said phenyl is optionally substituted with one to threesubstituents each independently selected from the group consisting of:halo, hydroxyl, cyano,

NRR, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₃ alkoxy, and C₁₋₃ haloalkoxy;R^(9b) is optionally substituted C₃₋₆ cycloalkyl, optionally substitutedphenyl or optionally substituted heterocyclic, said C₃₋₆ cycloalkyl andheterocyclic are each optionally substituted with one to foursubstituents each independently selected from the group consisting of:hydroxyl, CH₂OH, —NRR, —NRC(O)CH₃, 4 to 6 membered heterocyclic, cyano,halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, and C₁₋₃ alkoxy, and said phenyl isoptionally substituted with one to three substituents each independentlyselected from the group consisting of: halo, hydroxyl, cyano, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₃ alkoxy, and C₁₋₃ haloalkoxy; and each R isindependently selected from the group consisting of H, C₁₋₃ alkyl andC₃₋₆ cycloalkyl; or a pharmaceutically acceptable salt thereof.
 2. Thecompound according to claim 1 wherein R³ and R⁴ are both hydrogen; or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 1 wherein R¹ is hydrogen; or a pharmaceutically acceptable saltthereof.
 4. The compound according to claim 1 according to formula (II):

or a pharmaceutically acceptable salt thereof.
 5. The compound accordingto claim 1 wherein: R⁵ is hydrogen or halo; and R⁶ is hydrogen, halo,methyl, CH₂F, CHF₂, or CF₃; or a pharmaceutically acceptable saltthereof. 6.-8. (canceled)
 9. The compound according to claim 1 whereinR^(2a) is methyl; or a pharmaceutically acceptable salt thereof.
 10. Thecompound according to claim 1 wherein R^(2b) is OH, fluoro, methoxy,t-butoxy, CHF₂, CF₃, NH₂ or NH(CH₃); or a pharmaceutically acceptablesalt thereof.
 11. The compound according to claim 1 having the followingformula:

wherein R^(2b) is OH, NH₂ or fluoro; or a pharmaceutically acceptablesalt thereof.
 12. The compound according to claim 1 according to formula(IV):

wherein R^(2b) is OH or NH₂; or a pharmaceutically acceptable saltthereof. 13.-14. (canceled)
 15. The compound according to claim 1according to formula (V):

or a pharmaceutically acceptable salt thereof.
 16. The compoundaccording to claim 15 wherein R^(2a) is methyl; or a pharmaceuticallyacceptable salt thereof.
 17. The compound according to claim 1 whereinR⁷ is:

or a pharmaceutically acceptable salt thereof. 18.-19. (canceled) 20.The compound according to claim 1 wherein R⁹ is pyrazolyl, pyridinyl,indolyl or isoquinolinyl each of which is optionally substituted; or apharmaceutically acceptable salt thereof.
 21. (canceled)
 22. Thecompound according to claim 1 according to formula (IV)

wherein: R^(2b) is OH; R⁵ is hydrogen or fluoro; R⁶ is hydrogen, chloro,methyl or CH₂F; R⁷ is

R⁸ is hydrogen, methyl or fluoro; n is 1 or 2; and R⁹ ismethylcyclopropyl, isobutoxy, phenyl optionally substituted with one ortwo substituents each independently selected from the group consistingof: fluoro, chloro, bromo, C₁₋₄ alkyl, CF₂H and CF₃ or pyridinyloptionally substituted with one or two substituents each independentlyselected from the group consisting of: methyl, CF₃ and C(CH₃)₂CF₃; or apharmaceutically acceptable salt thereof. 23.-24. (canceled)
 25. Thecompound according to claim 1 according to formula (VI)

wherein: R^(2b) is fluoro; R⁵ is hydrogen or fluoro; R⁶ is hydrogen; R⁷is

R⁸ is hydrogen or methyl; n is 1; and R⁹ is phenyl optionallysubstituted with one chloro; or a pharmaceutically acceptable saltthereof. 26.-34. (canceled)
 35. The compound according to claim 1 whichis(R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-oneor a pharmaceutically acceptable salt thereof.
 36. The compoundaccording to claim 1 which is(R)-3-(5-fluoro-2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-oneor a pharmaceutically acceptable salt thereof. 37.-38. (canceled)
 39. Apharmaceutical composition comprising a compound according to claim 1,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.
 40. A method for the treatment of adisease or disorder associated with a mutant IDH protein having aneomorphic activity comprising administration of a therapeuticallyeffective amount of a compound according to claim 1, or apharmaceutically acceptable salt thereof, to subject in need of thereof.41. A method for the treatment of a disease or disorder associated witha mutant IDH protein having a neomorphic activity comprisingadministration of a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, andanother therapeutic agent to subject in need of thereof.